Table 2.
Involvement of MAM proteins in HD.
| MAM Proteins | Functions of Proteins during HD | Reference |
|---|---|---|
| Drp 1 | Aberrant Drp1-mediated mitochondrial fragmentation within the striatum of HD mutant mice, forces mitochondria to place far away from the ER disrupting the ER-mitochondria association and therefore causing changes in Ca2+ efflux and an excessive production of mitochondria superoxide species. | Cherubini et al., 2020 |
| PERK | There is a strong ER stress induction and UPR activation in striatal neurons expressing mHtt. PERK pathway is strongly downregulated in striatal neurons compared to other cell types and brain regions in WT mice and is upregulated in HD. PERK activation is an effective and selective strategy to reduce ER stress, re-establish ER homeostasis and increase the survival of cells and mice expressing mHtt. | Ganz et al., 2020 |
| RyR 2 | RyR channels were oxidized, PKA phosphorylated, and leaky in brain, heart, and diaphragm both in patients with HD and in a murine model of HD. Defective RyR function has been reported in HD, leading to elevated intracellular Ca2+ levels and reduced endoplasmic reticular Ca2+ stores in R6/2 striatal and cortical neurons . | Dridi et al., 2020 |
| ATAD3A | In HD, ATAD3A forms oligomers which bridge Drp1-mediated mitochondrial fragmentation and mtDNA instability, leading to impaired mitochondrial biogenesis and neurodegeneration. | Zhao et al., 2019 |
| Fis 1 | Heart is highly susceptible to the effects of mHTT. Drp1 hyperactivation through its interaction with Fis1 plays a role in the pathogenesis of polyglutamine induced cardiac mitochondrial dysfunction. Inhibitor for Drp1/Fis1 interaction, reduced pathological mitochondrial fission in mouse and human cell models of HD. | Joshi et al., 2018 |
| CHOP | mHtt expressing striatal cells also exhibited enhanced ER stress in response to serum deprivation, indicated by upregulation of CHOP. The upregulation of CHOP can also downregulate Bcl2 and upregulate pro-apoptotic Bax and Bak. Increase in CHOP expression leads to oxidative stress response in the cells. | Zhou et al., 2018 |
| DISC1 | Disturbance of DISC1-PDE4 interactions and behavioral changes through aggregation of DISC1 in HD.HTT forms a ternary protein complex with the scaffolding protein DISC1 and cAMP-degrading phosphodiesterase 4 (PDE4) to regulate PDE4 activity. Aggregation of DISC1 is significantly accelerated by the presence of mutant HTT, and they recapitulate the PolyQ pathology of HD. Cross-seeding of mutant HTT and DISC1 and the resultant changes in PDE4 activity may underlie the pathology of a specific subset of mental manifestations of HD. | Tanaka et al., 2017 |
| OPA 1 | Integrity of the mitochondrial cristae is compromised in striatum and cortex of the HD mice and that this is most likely caused by impaired OPA1 oligomerisation. Mutant huntingtin reduces OPA1 gene expression and promotes OPA1 cleavage. | Hering et al., 2016 |
| VDAC 1 | The expression of mHtt may promote VDAC closing, a situation known to be accompanied by changes of VDAC selectivity toward cations. This, in turn, may influence metabolite exchange between mitochondria and cytoplasm. Decreased conductance of the open state and decreased voltage-dependence reflect VDAC functional changes occurring in cells with expression of mHtt. | Karachitos et al., 2016 |
| PINK1 | PINK1 overexpression alleviated mitochondrial spheroid formation. Mitophagy is altered in the presence of mHtt and that increasing PINK1/Parkin mitochondrial quality control pathway may improve mitochondrial integrity and neuroprotection in HD. | Khalil et al., 2015 |
| mTOR | Htt promotes signaling by mTORC1 [mechanistic target of rapamycin (mTOR) complex 1] and that this signaling is potentiated by poly-Q–expanded Htt. Htt promotes amino acid mediated mTORC1 signaling that stimulated the interaction of Htt and the guanosine triphosphatase (GTPase) Rheb (a protein that stimulates mTOR activity), and that Htt forms a ternary complex with Rheb and mTOR. | Pryor et al., 2014 |
| Sigma- 1 Receptor | Sig-1R protein levels were decreased in mutant huntingtin-expressing cells. Partial co-localization of Sig-1R with aggregates in mutant huntingtin protein-expressing cells were observed, suggesting that the Sig-1R may be redistributed or delocalized in these cells. | Hyrskyluoto et al., 2013 |
| IRE1 | Regulates mutant huntingtin (HTT) clearance and most studies have shown that IRE1 can control autophagy levels by recruiting the adaptor protein TRAF2 and activating MAPK8 (mitogen-activated protein kinase 8)/JNK | Fouillet et al, 2012; Paolo Remondelli and Maurizio Renna 2017 |
| IP3R | Mutant huntingtin bind to the carboxy-terminal region of the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) and causes sensitization of IP3R1 to activation by IP3 in planar lipid bilayers and in neuronal cells. InsP3R1 association of ER stress chaperone protein GRP78 is impaired in Huntington’s disease R6/2 model mice, resulting in misregulation of InsP3R1 gating. Impairment of IP3R1 function promotes mitochondria-dependent cell death in the model mice by producing negative effects on mitochondrial Ca2+, the membrane potential and depletion in mitochondrial ATP production. | Higo et al., 2012 |
| Mfn 1 | Levels of Mfn 1 was decreased in mutant Htt neurons, confirming the presence of abnormal mitochondrial dynamics in the cortex of HD patients, and may contribute to neuronal damage in HD patients | Shirendeb et al., 2011 |
| Fis 1 | FIS1 was highly associated with late-stage HD rather than the pre-symptomatic stage. Fis1 recruits Drp1 under cell stress in numerous neurodegenerative disease models. In HD, the balance between fusion and fission is aberrantly shifted toward fission, which is associated with increased levels of Fis1 mRNA and decreased mitofusins in striatal and cortical regions, leading to mitochondrial fragmentation. | Shirendeb et al., 2011; Xiang et al., 2020 |
| Mfn 2 | Mfn2 can directly interact with the N-terminus of mutant Htt, suggesting that Htt can interfere directly with the function of Mfn2 in the promotion of mitochondrial elongation and in the regulation of the apoptotic function of Bax. Mutant Htt, also interfere with the extramitochondrial functions of Mfn2, leading to alterations in the shape of the ER, in the ER levels of Ca2 þ , and last but not least in the tethering of mitochondria to the ER. | Wand et al., 2009; de Brito OM and Scorrano L (2008) |
| ITPR 1/3 | The polyQ-Htt can bind ITPR1 with high affinity, sensitizing the receptor activity by IP3. Blocking the Htt–ITPR1 interaction in vivo was shown to regulate the abnormal calcium signaling in response to glutamate, protecting the neurons from death, and improving motor coordination | Tang et al., 2009 |
| PP2A | Several holoenzyme complexes of PP2A have been isolated from a variety of tissues and have been extensively characterized. PP2A consists of a regulatory subunit termed as PR65. The structure of PR65 is unusual, since it is entirely composed of 15 tandem repeats of a 39-amino-acid sequence, termed as HEAT (huntingtin elongation A subunit TOR, where TOR is target of rapamycin) motif. HEAT sequence is present in huntingtin protein, an elongation factor required for protein synthesis and the TOR kinase. These domains play a role in a variety of interactions between proteins. | Hiroki Takano and James F Gusella 2002 |
| Grp 75 | The interaction between calcium channel IP3R and VDAC1 in the outer mitochondrial membrane is strengthened by Grp75. Compared with Wild type mice, a significant decrease in Grp75 levels was observed in R6/1mice at 12 and 20 weeks of age. | Cherubini et al., 2020 |