Mitochondria–lysosome crosstalk in GBA1-associated Parkinson’s disease

Abstract

Organelle crosstalk is significant in regulating their respective functions and subsequent cell fate. Mitochondria and lysosomes are amongst the essential organelles in maintaining cellular homeostasis. Mitochondria–lysosome connections, which may develop dynamically in the human neurons, have been identified as sites of bidirectional communication. Aberrancies are often associated with neurodegenerative disorders like Parkinson's disease (PD), suggesting the physical and functional link between these two organelles. PD is often linked with genetic mutations of several mutations discovered in the familial forms of the disease; some are considered risk factors. Many of these genes are either associated with mitochondrial function or belong to endo-lysosomal pathways. The recent investigations have indicated that neurons with mutant glucosylceramidase beta (GBA1) exhibit extended mitochondria–lysosome connections in individuals with PD. This may be due to impaired control of the untethering protein, which aids in the hydrolysis of Rab7 GTP required for contact untethering. A GCase modulator may be used to augment the reduced GBA1 lysosomal enzyme activity in the neurons of PD patients. This review focuses on how GBA1 mutation in PD is interlinked with mitochondria–lysosome (ML) crosstalk, exploring the pathways governing these interactions and mechanistically comprehending the mitochondrial and lysosomal miscommunication in the pathophysiology of PD. This review is based on the limited literature available on the topic and hence may be subject to bias in its views. Our estimates may be conservative and limited due to the lack of studies under the said discipline due to its inherent complex nature. The current association of GBA1 to PD pathogenesis is based on the limited scope of study and further research is necessary to explore the risk factors further and identify the relationship with more detail.

Introduction

Parkinson's disease (PD) is a progressive neurological ailment that manifests itself through tremor, bradykinesia, muscular stiffness, poor gait, and postural instability (Rai and Singh 2020; Rai et al. 2020, 2021a, b). Half of the people with PD have frontostriatal-mediated executive dysfunction, including problems with attention, mental processing, verbal fluency, memory, and impulse control. The loss of dopaminergic neurons in the substantia nigra (SN) and depletion of dopamine (DA) levels in the striatum are the hallmarks of PD (Dauer and Przedborski 2003). Experimental pieces of evidence demonstrate that the prefrontal cortex (PFC), anterior cingulate gyrus, and frontostriatal pathways are likewise affected by PD (Maiti et al. 2017).

The prevalence of PD is estimated to be 9.4 million worldwide, with nearly 1% of the geriatric population suffering (Foundation 2019). The increasing PD prevalence in the ageing population is of genuine concern. Globally, the burden of PD has grown considerably from 2.5 million people in the year 1990 to 6.1 million in 2016 (Ray Dorsey et al. 2018). India alone reported nearly 0.58 million PD patients in 2016, with a significant increase expected in the years to come (Rajan et al. 2020).

PD is a highly heterogeneous disorder with various clinical manifestations. Researchers suggest that the clinical subtypes of PD, including psychiatric and cognitive features (not the motor deficits alone), should drive PD subtype classification. The predictive value of the PD subtypes was demonstrated by differences in dementia and mortality rates across these subtypes (Campbell et al. 2020).

Mitochondrial and lysosomal dysfunction have a synergistic effect in PD as their compartments are so interlinked that a primary defect in one causes the other compartment to malfunction (Demers-Lamarche et al. 2016). The growing link between lysosomal disorders and PD emphasizes the importance of lipid homeostasis in the pathogenesis of the disease (Guerra et al. 2019a). The recent studies linked mitochondria–ER contact sites with PD pathogenesis by discovering Vacuolar Protein Sorting 13 Homolog C (VPS13C) as a lipid transporter between these two organelles (Kumar et al. 2018). The buildup of misfolded protein aggregates, failure of protein clearance mechanisms, mitochondrial damage, oxidative stress, excitotoxicity, neuroinflammation, and genetic alterations all contribute to the pathophysiology of PD (Williams et al. 2017). The present review aims to reappraise the mitochondria–lysosome crosstalk and the impact of the Glucosylceramidase Beta (GBA) gene in the pathogenesis of PD, based on the past and contemporary evidence and findings.

Role of GBA gene mutation in PD

PD pathogenesis is associated with genetic and nongenetic risk factors. The nongenetic risk factors are summarized in Table 1.

Table 1.

Nongenetic factors in PD

Risk Factors with certainty in linkage (Das et al. 2011; Rizek et al. 2016; Tysnes and Storstein 2017; Calne et al. 2022)

Gender

Age

Hereditary (Presence of first-degree relative)

Environmental factors

Risk factors with positive linkage (Martino et al. 2017)

Head Injury

Rural living

Mental health issues (anxiety/depression)

Pesticide poisoning/consumption

Dairy product consumption

Risk factors with questionable linkage (Liu et al. 2012; Qi 2014; Breckenridge et al. 2016)

Physical inactivity

Smoking

Coffee/alcohol consumption

Increase in uric acid concentration

Numerous studies indicate that around 5–10% of late-onset types of PD are caused by hereditary factors (Day and Mullin 2021). Numerous variations of genes related to the aetiology of PD have been found in the recent years. Nearly 23 PARK genes have been related to PD, with either autosomal dominant or autosomal recessive mutations in PARK genes, as listed in Table 2 (Schulte and Gasser 2011). PRKN, PINK1, and PARK7, for example, are all genetic regulators of mitochondrial activity (Correia Guedes et al. 2020). ARSA, LRP10, NUS1, and TMEM230 have been proposed to cause PD, in addition to the previously researched genes involved in Mendelian PD (Vilariño-Güell et al. 2014a; Deng et al. 2016a). Table 2 provides an overview of PD causative genes.

Table 2.

Genetic factors in the epidemiology of PD

Type of Genes	Locus	Form of PD	References
SNCA LRRK2 VPS32	PARK1, PARK4 PARK8 At2g19830	Autosomal Dominant	(Xi et al. 2021a)
PRKN PINK-1 DJ-1 GWAS	PARK2 PARK6 PARK7 BSTI, HLA	Autosomal Recessive	(Xi et al. 2021a)
Glucocerebrosidase	GBA1	Recessive	(Wong et al. 2018; Prajapati et al. 2018)
Theoretically proposed genes	TMEM 230, LRP 10, NUS 1, ARSA		(Vilariño-Güell et al. 2014b; Deng et al. 2016b)
Classic Mendelian Genes	FBX 10, LA2G6, VPS13C and CHCHD2	Atypical PD (Burchell et al. 2013)	(Burchell et al. 2013)
Causative of Levodopa side-effects	DDC, COMT, DAT, DRD2, DRD3		(Bialecka et al. 2008)
Controversial genes related to PD	DNAJ6, SMPD1, SYNJ1, DNAJC13, TMEM 230, RIC3, VPS13C, NUS1, ARSA		(Zhu et al. 2015; Fernández-Santiago et al. 2019)

ARSA Arylsulfatase A, BSTI Bombina skin trypsin/thrombin inhibitor, HLA Human leukocyte antigen, CHCHD2 Coiled-coil-helix-coiled-coil-helix domain containing 2, COMT Catechol-O-methyltransferase; DAT: Direct antiglobulin test; DDC: Dopa decarboxylase; DJ-1: Protein deglycase; DNAJ6: DnaJ homolog subfamily B member 6; DNAJC13: DnaJ (Hsp40) homolog, subfamily C, member 13; DRD2:Dopamine receptor D2; DRD3: Dopamine receptor D3; FBX 10: F-Box Protein 10; GBA1: Glucocerebrosidase 1; GWAS: Genome-wide association studies; PLA2G6: phospholipase A2 group VI; LRP 10: LDL receptor-related protein 10; LRRK2: leucine-rich repeat kinase 2; PARK: Parkinsonism associated deglycase; PINK-1: PTEN induced kinase 1; PRKN: Parkin RBR E3 ubiquitin protein ligase; RIC3: resistance to inhibitors of cholinesterase 3; SMPD1: sphingomyelin phosphodiesterase 1; SNCA: synuclein alpha; SYNJ1: Synaptojanin 1; TMEM 230: Transmembrane Protein 230; VPS13C: Vacuolar protein sorting-associated protein 13C; VPS32: Vacuolar protein sorting-associated protein 32

When compared with other genetic mutations, a mutation in the glucocerebrosidase (GBA) gene is the most prevalent genetic risk factor for PD (PARKIN2) (Sidransky and Lopez 2012). The GBA gene codes for glucocerebrosidase (GCase), a lysosomal enzyme. The risk factor of GBA mutation was discovered during a clinical trial on Gaucher's disease (GD) patients, a rare lysosomal storage disorder (Sidransky and Lopez 2012). GBA mutations have been linked to various α-synucleinopathies, including PD, Lewy Body dementia, and, more recently, multiple system atrophy type C (Brockmann 2020). The above findings; thus, indicate that α-syn accumulation is due to the decreased G-case activity caused by GBA-1 mutation.

Individuals with a GBA gene mutation have a 21-fold increased chance of developing PD over their lifespan. GBA mutations were shown to be twice as prevalent in patients with early-onset PD (age less than 50 years) as in those with late-onset (older than 50 years) (Sidransky and Lopez 2012). In addition, a randomized clinical trial (RCT) of glial cell line-derived neurotrophic factor (GDNF) in PDGBA found that carriers of the mutation are more likely than noncarriers to acquire dementia (Nutt et al. 2003). However, multiple additional studies linked GBA mutations to higher rates of cognitive decline, bradykinesia, olfactory impairment, and less stiffness (Sidransky and Lopez 2012).

The specific mechanisms that lead to parkinsonism caused by GBA are unknown. Scientists suggest that GBA mutations reduce GCase activity, resulting in autophagic–lysosomal dysfunction and the buildup of α-synuclein aggregates (Bae et al. 2015). Furthermore, GBA1 deficiency was reported in numerous models and people and linked with the establishment of α-synuclein accumulation and aggregation (Maor et al. 2019; Polinskii et al. 2021). GBA1-related neurodegeneration in PD is also anticipated due to mitochondrial malfunction resulting from faulty mitochondria mitophagy because of toxins buildup (Cullen et al. 2011; Osellame et al. 2013; Murphy et al. 2014). Autophagy abnormalities have been observed in iPSC-derived neurons from PD patients with GBA1 mutations (Schöndorf et al. 2014). Further research is needed to explore these processes and discover related risk factors that work in tandem with GBA to favour Parkinsonism progression.

Mitochondrial and lysosomal dysfunction—synergistic effect in PD

Several genes that cause or increase the risk of PD are associated with lysosomal and mitochondrial dysfunction. The lysosomal and mitochondrial compartments are so tightly coupled that a deficiency in one compartment results in malfunction in the other (Demers-Lamarche et al. 2016). The emerging associations between lysosomal disorders and PD emphasize the role of lipid homeostasis in PD pathogenesis (Guerra et al. 2019a). The recent studies linked the mitochondria-ER contact sites with PD pathogenesis via discovering VPS13C as a lipid transporter between these two organelles (Kumar et al. 2018). Moreover, the same transcriptional regulation is observed in mitochondria and lysosomes' biogenesis, which plays a vital role in the crosstalk between these two organelles. Alteration in the protein levels of TFEB, the lysosomal transcription factor, and PGC1α, the mitochondrial transcription factor, result in PD gene abnormalities and organelle dysfunction. Despite the new data, essential gaps in our knowledge of the physical and functional relationships among various PD-associated pathways persist (Williams et al. 2017). The ML contact sites provide crucial insight into the bidirectional interaction and may assist to explain the convergence of malfunction in both organelles in Parkinson's disease.

Previously published research established that the mitochondrial genes PINK1, PARK2 (PARKIN), DJ-1 (PARK7), and leucine-rich repeat kinase 2 (LRRK2), all of which control ROS homeostasis, contribute essentially to PD (Valente et al. 2004; Nichols et al. 2005; Guzman et al. 2010). PARKIN's E3 ubiquitin ligase activity is activated by PINK1 buildup in the mitochondria, attracting PARKIN into the damaged mitochondria and selectively clearing the damaged mitochondria by autophagy (Lazarou et al. 2012; Xi et al. 2021a). An old study revealed the role of mitochondrial dysfunction in PD when numerous drug addicts self-injected 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Environmental exposure to the neurotoxin MPTP, a mitochondrial CI inhibitor, caused ATP depletion, ROS production, dopaminergic neuron degeneration, and PD (Langston et al. 1983). The study of MPTP is critical to learning molecular and cellular pathways in the genesis of PD (Ferrucci and Fornai 2021). 1-methyl-4-phenylpyridinium (MPP), the bioactive form of MPTP, inhibits Complex I (CI) of the Electron Transport Chain (ETC) in mitochondria, resulting in increased ROS production (Guardia-Laguarta et al. 2015; Guerra et al. 2019b). Several investigations demonstrated that intoxicants affect mitochondrial respiratory CI activity in PD models in vivo and in vitro, as well as in human parkinsonism (Schapira et al. 1990; Papa and Rasmo 2013).

Depletion of PINK1 results in lysosomal dysfunction and compartment enlargement. Suppression of mitochondrial ATP synthase by oligomycin (Ysselstein et al. 2019) and TFAM deletion, the primary transcription factor for mitochondrial biogenesis, resulted in lysosomal compartment abnormalities (Baixauli et al. 2015; Demers-Lamarche et al. 2016). Additionally, the PD-related protein DJ-1, found in mitochondria, is implicated in mitochondrial function and autophagy. These findings suggest that mitochondrial quality control, dynamics, and respiration might influence lysosomal function in PD (Guerra et al. 2019b). Damaged mitochondria can only be turned via the autophagy–lysosomal system (Ashrafi and Schwarz 2013). Therefore, any interruption in autophagy or lysosomal dysfunction could cause, if not exacerbate, mitochondrial malfunction. Autophagy–lysosomal dysfunction disrupts mitochondrial homeostasis, which, in turn, affects lysosomal activities, implying a complicated link between these processes. As discussed earlier in this section, the lysosomal and mitochondrial compartments are so well linked that an issue in one compartment causes the other compartment to malfunction (Park et al. 2018). A miRNA expression analysis used to investigate the role of miRNAs in PD pathogenesis revealed a link between the two pathways—MiR-5701 was significantly downregulated in SH-SY5Y cells exposed to 6-hydroxydopamine, and miR-5701's likely targets include genes involved in lysosomal biogenesis and mitochondrial quality control (Prajapati et al. 2018). Hence, mitochondria and lysosomes are essential for cellular homeostasis, and abnormalities that are genetically and physiologically associated with PD have now been discovered. The figure below presents the role of ML crosstalk in the pathogenesis of PD Fig. 1.

Fig. 1.

The functional relationship of ML crosstalk in PD pathogenesis. The figure depicts several communication channels between mitochondria and lysosomes. The receptors and connection sites between these organelles are identical, implying that the end organelles operate similarly. Mitophagy, mitochondrial-derived vesicles (MDVs), mitochondrial-derived compartments (MDCs), and membrane contact sites ((MCS) are the key functional interactions between mitochondria and lysosomes. Mitophagy begins with stressed and malfunctioning mitochondria; when the membrane potential of the damaged mitochondria decreases, PINK1 is stabilized, and enzymes are activated (PRKN, LRRK-2, GBA). This further activates the mitochondria digestion into lysosomes, which results in the specific release of MDC and MDV. The release of these chemicals further increases the biogenesis of lysosomes, impairs the replication and some of which lack quality control checkpoints that make them faulty. All these together lead to increased production of the naturally occurring alpha-syn protein. These proteins produce Lewy bodies, which is a confirmatory pathway to PD pathogenesis. (Thelen and Zoncu 2017; Farmacologiche 2018; Ugur et al. 2020)

GBA1 dysfunction leading to dysregulation of mitochondria–lysosome contacts

Recently, mitochondria–lysosome (ML) connections were found in the cell body, axons, and dendrites of human nerve cells for bidirectional interaction via tethering of both the organelles (Wong et al. 2018, 2019). The mutant neurons in GBA1-PD patients exhibited decreased levels of GCase protein and diminished activity in idiopathic and familial PD patients, indicating that targeting GBA1 may be a possible treatment strategy for PD (Wong et al. 2018, 2019). GCase pathway in the hunt for Parkinson's disease biomarkers and biological targets that may aid in developing disease-modifying treatments.

The recent research established the role of disrupted ML contact dynamics in human neurons in the aetiology of GBA1-associated PD. (Kim et al. 2021). Reduced GCase lysosomal enzyme activity impairs contact untethering and prolongs ML connections in dopaminergic neurons generated from PD patients expressing heterozygous mutant GBA1. The abnormal ML contact was caused by aberrant regulation of TBC1D15, the untethering protein involved in Rab7 GTP hydrolysis, which eventually affected mitochondrial distribution and function. TBC1D15 may correct abnormalities in PD patients with GBA1-linked neurons, demonstrating the critical significance of ML contact sites in human neurons and the pathogenesis of GBA1-linked PD.

In addition, the study indicated no change in the localization of TBC1D15 and Fis1 to mitochondria, Rab7 to lysosomes, or the amounts of the Rab7 GEF (guanine nucleotide exchange factor) complex proteins in mutant GBA1 neurons. TBC1C15 levels, on the other hand, were considerably lowered in mutant GBA1 neurons, suggesting that down regulation of TBC1D15 levels disturbs Rab7 GTP hydrolysis; hence, increasing GTP-bound Rab7 and extending ML contact tethering dynamics. Proteasomes degraded TBC1D15 in mutant GBA1 neurons due to the absence of GCase activity. This was corroborated in another experiment, where reducing GCase activity with conduritol-b-epoxide (CBE) resulted in increased length of ML contact tethering. The average duration of ML contacts in mutant GBA1 and CRISPR-corrected isogenic tethering control neurons was compared and revealed that while ML contacts formed dynamically in both conditions, the average duration of ML contact tethering increased significantly in mutant GBA1 neurons, indicating inefficient untethering events. The study revealed that the absence of GCase activity impairs ML contact site untethering and not ML contact creation, ensuing in an extended contact site tethering between the two organelles.

Furthermore, the fact that ML contact dynamics were not impacted by other lysosomal enzymes' alteration in human neurons indicated that the abnormal ML contact dynamics were due to diminished GCase activity. The researchers could also prevent extended ML contact tethering in mutant GBA1 neurons using S-181 therapy to boost GCase activity in mutant GBA1 neurons (Burbulla et al. 2019). In addition, the importance of GCase in controlling ML contact dynamics was emphasized.

Prodromal PD attributes in GBA1 carriers

The GBA1 metabolic pathway is a promising target to protect neuronal damage in PD (Mazzulli et al. 2011; Gegg and Schapira 2016). Hence, assessing PD prodromal features in GBA1 carriers might identify and prevent these high‐risk individuals from converting to PD.

A recent cross‐sectional and longitudinal study that examined prodromal PD signs among GBA1 carriers concluded that olfactory and cognitive function and the UPDRS II and III scores were significantly higher, and progression to microsomia and mild cognitive impairment was more rapid in GBA mutation carriers than controls (Mullin et al. 2019). However, there were no significant differences in RBDSQ scores. The study used Risk Stratification Procedure for clustering of Prodromal PD symptoms, which considered the progression and severity of each prodromal feature. In general, the olfactory disturbance was clustered with impaired cognition and depression. However, in biallelic GBA1 carriers, the olfactory dysfunction clustered only with impaired cognition but not depression.

Over 6 years, another longitudinal investigation examined prodromal PD characteristics in individuals with type 1 GD, heterozygous GBA1 mutation (Het GBA), and GBA-negative controls (HC) (Avenali et al. 2019). The study found that scores on most clinical measures, including the UPSIT, UMSARS, MDS-UPDRS III, MOCA, RBDsq, and BDI, deteriorated with time in the GD and Het GBA groups. In addition, these groups had severe declines in olfactory function, motor function, and cognitive function, indicating that GBA1 mutations had a significant impact on early clinical indicators of neurodegeneration. These clinical indicators were significantly linked with baseline clinical features, indicating that severe microsomia may be a compelling indication of motor and nonmotor symptom progression.

Similarly, olfactory dysfunction may be considered a prognosis of PD, although the GCase activity could not be associated with any clinical markers. Table 3 summarizes all the cardinal clinical features of GBA-associated PD. The updated MDS study criteria for prodromal PD imply that direct visualization of the substantia nigra with neuroimaging is a sensitive and specific marker of prodromal PD in conjunction with RBD, GBA/LRRK2 mutation carriers, Lewy Body Dementia, and PD (Barber et al. 2017; Heinzel et al. 2019). Nonmotor symptoms emerge 2–10 years before motor symptoms, and GBA1 bearers are related to nonmotor symptoms, such as olfactory function and cognitive impairment. Therefore, it is possible that these GBA carriers recognize these prodromal symptoms and protect them from a high risk of PD.

Table 3.

Clinical features in GBA-associated PD

Clinical features in GBA-associated PD (Zhang et al. 2018; Malek et al. 2018)

Earlier age of onset of PD

Have PIGD phenotype

Severe motor impairment

Higher (UPDRS)-III scores

Increased risk of having a family history, dementia, depression, wearing-off

No differences in cognitive function and global cognition score when compared with noncarriers

PIGD postural instability and gait difficulty, UPDRS unified Parkinson disease rating scale

Latest therapeutic advances and treatment strategies in GBA-PD

GBA-PD patients respond well to L-Dopa, particularly in the early stages of the illness, although motor symptoms seem to develop more quickly than in iPD. Therefore, a particular treatment approach must be explored for these individuals. Owing to their inability to pass the blood–brain barrier, therapeutic strategies for systemic signs of GD have no effect on glycosphingolipid buildup in the central nervous system. Contemporarily, the following table details the experimental methods currently accessible in clinical trials.

The primary theory suggests that the mutated versions of GBA are unable to fold correctly in the endoplasmic reticulum (ER) of cells, leading the protein to accumulate in this cellular compartment. This would induce a stress response in dopaminergic neurons, resulting in their destruction and death. In addition, the trapping of beta GCase in the ER reduces the enzyme's levels in the cells, resulting in the buildup of alpha-synuclein(McNeill et al. 2014). Different chaperones, which are proteins able to aid the refolding of their substrates, were evaluated in an attempt to target this pathogenic process (McNeill et al. 2014; Ambrosi et al. 2015; Sanchez-Martinez et al. 2016; Migdalska-Richards et al. 2016, 2017). In 2016, clinical research evaluating the effectiveness of Ambroxol, one of these chaperones whose first findings were quite encouraging, was initiated. This is a phase 2 clinical study designed to evaluate the safety and effectiveness of this medicine in improving motor and cognitive symptoms in PD patients with a GBA mutation. The research is now in progress. Allergan has conducted a phase 1 trial using LTI-291, a chaperone molecule with the ability to boost the activity of GCase. Isofagomine is an additional chaperone protein that has been evaluated in vitro and in vivo for its capacity to alter the phenotype caused by GBA mutations (Sanchez-Martinez et al. 2016). This molecule serves to stabilize GCase as an inhibitory chaperone.

The buildup of glucosylceramide (the substrate typically eliminated by GCase) in dopaminergic neurons (due to the mutation of GBA) is the second pathway that has been investigated for treating GBA–PD patients (Sardi et al. 2011; Bae et al. 2014; Fernandes et al. 2016). (Recently, Genzyme initiated a multicenter, randomized, double-blind, placebo-controlled phase 2 study to evaluate the safety, pharmacokinetics, and pharmacodynamics of an oral compound, Ibiglustat (GZ/SAR402671), that can decrease the levels of beta-glucocerebrosidase in GBA carriers with early-stage PD.

In addition, there is still a long way to go before establishing a viable therapy for Parkinson's disease, but several avenues have been identified, providing individuals with PD, a hope for therapeutic remission. The mutated GCase is more unstable than its wild-type counterpart. Therefore, manipulation of GCase degradation might be another viable technique for enhancing the enzyme's activity and so combating alpha-synuclein buildup and neurodegeneration.

Several neuroprotective compounds have been discovered and extracted from medicinal herbs for the efficient treatment of Parkinson's disease; some of them are described in this section. The recent research has shown the substantial neuroprotective impact of medicinal plant extracts and phytochemicals in reducing PD symptoms owing to their antioxidant and anti-inflammatory capabilities (Javed et al. 2019). Ursolic acid, a naturally occurring pentacyclic triterpenoid carboxylic acid, is one of them. It is found in several plants, including apples, basil, bilberries, cranberries, peppermint, rosemary, and oregano (Rai et al. 2019).

Chlorogenic acid (CGA), a common polyphenolic molecule is found in several plants, and is especially abundant in green coffee beans having 5–12% CGA by weight. It primarily exerts its effects by downregulating the expressions of iNOS, TNF-α, and NF-κB in activated glial cells; therefore, reducing neuroinflammation through its enhanced anti-inflammatory and antioxidant capabilities (Singh et al. 2018) Table 4.

Table 4.

Current experimental methods accessible in clinical trials

Drug	Mechanism	Targeted patients	Registered clinical trial (clinicaltrials.gov)	Phase	Status
Venglustat (GZ/SAR402671)	Glucosyylceramide synthase inhibitor	GBA-PD	NCT02906020	II	Due to the negative effect on clinical phenotype study is halted
Ambroxol	Inhibitory chaperone that Increases GCase activity	sporadic PD and GBA-PD	NCT02941822	II	In terms of safety and target engagement the outcome is positive
Ambroxol		PD-dementia	NCT02914366	II	Study in process
LTI-291	GCase activator facilitates GCase activity	GBA-PD	–		Study in process
PR001	Mutated GBA replaced with copy of gene WT	GBA-PD	NCT04127578	1/2a	Recovery of GCase activity, Preliminary report and Possible severe immune response

Neuroprotective effect of medicinal herbs for Parkinson’s disease

Similarly, Mucuna pruriens ameliorated MPTP-induced neuroinflammation and corrected biochemical and behavioural deficits in a mouse model of Parkinson's disease (Rai et al. 2017). Table 5 displays some of the medicinal plants that show promise as a therapeutic option for PD.

Table 5.

Therapeutic effects of medicinal plants and ingredients on PD

Medicinal plant/natural products	Model	Outcome
Mucuna pruriens	Rat	In substantia nigra endogenous-neurotransmitter (dopamine, L-dopa, serotonin and norepinephrine) is increased (Manyam et al. 2004)
Mucuna pruriens + Carbidopa	Mice	Free collateral rotation is improved when compared with L-dopa in 6-OHDA model(Singh et al. 2017)
Mucuna pruriens (Endocarp form HP 200)	Human	Induction of marked quantity of L-dopa accompanied with the decreased duration without change of dyskinesia intensity in L-dopa response with respect to standard dose of this drug (Katzenshlager et al. 2004)
Asiaticoside (CentellaAsiatica)	Rat	Dopaminergic neurons are protected and lessen the oxidative stress and motor dysfunction (Xu et al. 2012)
Curcumin	Transgenic mice	Activation of PI3K/AKT pathway and Bcl2 is increased (Sun et al. 2017)
Curcumin longa	Mice	MAO-A metabolising enzyme is inhibited (Yu et al. 2002)s
	SH-SY5Y Cells	Increase mitochondrial complex 1 activity and also decreases the caspase-3 activity in Salsolinol induced toxicity (Ma and Guo 2017)
Baicalein	Rat	Active caspase level is increased and caspase-3 and procaspase-1 is downregulated (Zhao et al. 2018)
Z. bungeanum	Mice	Avert the striatal p-AKT protein, tyrosine hydroxylase and dopamine decrease and caspase-3 and caspase 9 activation are attenuated. Activation of PI3K/AKT pathway (Zhao et al. 2020)
Cannabidiol	Human neuroblastoma cell lines SH-SY5Y	LC3 level is decreased. ERK and AKT/mTOR pathway is activated and modulate the autophagy (Gugliandolo et al. 2020)
Vicia faba.L	Human	Increase in the plasma L-dopa concentration and increase in the duration motor response in PD patients (Kempster et al. 1993)
Crocus sativus	Mice	In the substantia nigra and retina dopaminergic cells are protected and increase tyrosine hydroxylase in Substantial nigra pars compacta, locus coeruleus and dorsal striatum (Tamegart et al. 2019)

Discussion

Parkinson's disease (PD) is the most prevalent neurodegenerative movement illness, defined by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), resulting in the characteristic motor symptoms of PD. Both mitochondrial and lysosomal abnormalities have been genetically and functionally associated with PD. The recent studies have revealed mitochondria lysosome (ML) interface sites as inter-organelle membrane interactions involving the dynamic tethering of mitochondria to mediate lysosomes. Importantly, ML connections provide the bidirectional modulation of mitochondrial and lysosomal network dynamics, as well as their direct interaction in a route different from mitophagy or lysosomal destruction of mitochondrial-derived vesicles.

The subsequent mitochondria–lysosome contact disconnection is achieved by Rab7 GTP hydrolysis, which is preceded by the recruitment of cytosolic TBC1D15 (Rab7 GAP) to mitochondria by outer mitochondrial membrane protein Fis1 (Zhang et al. 2005; Onoue et al. 2013). Once recruited to mitochondria, TBC1D15 may interact with lysosomal GTP-bound Rab7 at mitochondria–lysosome contact sites to promote Rab7 hydrolysis to a GDP-bound form. GDP-bound Rab7 can no longer engage Rab7 effectors and loses its lysosomal membrane localization, resulting in mitochondria–lysosome contact detethering, perhaps via the loss of Rab7 effector tethering. The lysosomal enzyme GBA1, which encodes for -glucocerebrosidase (GCase) and catalyses the hydrolysis of glucosylceramide (GlcCer) to glucose and ceramide, is the most significant genetic risk factor for Parkinson's disease, with GBA1 mutation carriers displaying more severe cognitive symptoms (Sidransky et al. 2009; Sidransky and Lopez 2012). Mutant neurons generated from GBA1-PD patients have both decreased GCase protein levels and reduced GCase activity, and activation of GCase results in a drop in α syn, which lowers the downstream pathogenic effects on protein maturation and the lysosomal system. Furthermore, the activity of wild-type GCase is reduced in both idiopathic and different kinds of familial PD patient neurons (Schöndorf et al. 2014; Mazzulli et al. 2016). Therefore, targeting GBA1 may reveal potential disease-modifying therapeutic targets for Parkinson's disease. In this study, we focused on the importance of ML contact as a connection between mitochondrial and lysosome dysfunction and the relationship between mutant GBA1 and ML detethering in the development of Parkinson's disease.

Conclusion

Endo-lysosomal or mitochondrial abnormalities are linked to many genes associated with PD, either causing disease or increasing risk. The primary deficiency in one of the two compartments frequently harms the other, implying a robust reciprocal interaction contributing to the disease's pathophysiology. GBA1 mutations are critical in the molecular genesis of PD, and GCase deficiency may contribute to the development of PD. Low penetrance of PD with the GBA1 gene calls for larger retrospective cohorts to study incidences of PD conversion in GBA1 carriers. A combined study of GBA1 genotyping and prodromal PD symptoms could aid in identifying individuals at increased PD risk and target future neuroprotective medications. The pathobiological processes behind the relationship between GCase malfunction and the development of PD are currently unknown. However, interactions between α-synuclein and other proteins, lysosomal dysfunction, ER stress, and neuroinflammation may all play a role. Additional trials on larger GBA1-positive populations are necessary to deduce the molecular mechanisms underlying the association between GBA1 mutations and PD. These studies may lead to improved diagnosis and therapy by identifying potential therapeutic targets in the pursuit of new and customized methods for treating PD. As a result, more research into mitochondrial and lysosomal anomalies in PD aetiology is essential, as is the prospect of targeting key pathways as a universal therapy target for sporadic and familial PD.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.