Table 5.

Overview of established or potential CN involvement in human neurological and psychiatric disorders, with the corresponding genetic abnormalities, neuropathological changes, clinical features, and available murine models

Disorder	Etiology	Pathology and CN involvement	Clinical Features	Examples of mouse models (http://www.informatics.jax.org/allele)
Alzheimer’s disease (AD) [359]	Buildup of amyloid plaques and tau proteins	Bilateral atrophy in medial temporal regions (hippocampus and entorhinal cortex) and the superior parietal lobe. Within the cerebellum, AD patients show significantly higher levels of cell cycle markers and DNA damage response proteins in the Lat, indicative of cellular stress	AD is the most common neurodegenerative cause of dementia. Deficits include loss of episodic memory for recent events, loss of spatial memory, decreased performance at work, and word-finding difficulties. AD finally progresses toward a state of global dementia. Tremor, ataxia, deficits in speech, language, and motor planning are also observed	The triple-transgenic mouse model of AD (3xTg-AD), harboring two human transgenes causing early onset AD (PS1M146V and APPSwe) and a mutant form of tau (tauP301L), mimics both Aβplaques and tau neurofibrillary tangles, following a regional and temporal involvement homologous to humans. The 3xTg-AD cerebellar nuclei show a gradient of neural loss through the mediolateral axis, with the fastigial nucleus being the most affected area, followed by the interpositus nucleus, and the Lat not being affected. [360, 361]
Autism spectrum disorders (ASD) [362, 363]	Heterogeneous: most likely caused by a combination of genetic, epigenetic, and environmental factors during neurodevelopment	Cerebellar vermis hypoplasia, reduction of superior cerebellar peduncle, decreased connectivity of dentatorubrothalamic tract	Heterogeneous spectrum of clinical features affecting social interaction, communication, and behavior	Itgb3 KO (Itgb3tm1Hyn) [365], bilateral CN hypoplasia [366]; En2 KO (En2tm1Alj), enlarged superior cerebellar peduncle [367]; Fmr1 KO (Fmr1tm1Cgr/J) [368] Significantly decreased volume of the interposed and fastigial nuclei [369]
Dentato-olivary dysplasia with intractable seizures in Infancy [512, reviewed in 370]	Unknown; likely inherited as an autosomal recessive trait	Malformations of cortical development, pachygyria, polymicrogyria, and lissencephaly, cortical calcifications, attenuation of white matter, enlarged ventricles, hypoplastic corpus callosum, overfolded gyri, and glioneuronal heterotopia The Lat nuclei, appear as solid ovoid structures rather than as the characteristic thin, convoluted band	Hypotonia with frequent seizures from birth and gross developmental delays. Survival is no longer than 3 years	None
Dentatorubral- pallidoluysian atrophy (DRPLA)	Autosomal dominant neurodegenerative disease. Caused by a GOF mutation (expanded CAG triplet repeat) in the Atrophin 1 (Atn1) gene	Combined degeneration of the dentatorubral and pallidoluysian systems. The suffix “luysian” refers to the subthalamic nucleus, involverìd in the indirect pathway The globus pallidus, especially the lateral segment, and the Lat nuclei show loss of neurons and astrocytosis	Progressive disorder causing involuntary movements, mental and emotional problems, and a decline in cognitive abilities. Neurological signs include myoclonus, seizures, ataxia, choreoathetosis. Other signs include intellectual disability, dementia and psychiatric changes (e.g., delusions)	A transgenic line expressing truncated atrophin (Tg(Prnp-ATN1)150Dbo) [371]
Friedreich ataxia [372, 373]	Caused by autosomal recessive mutations in the frataxin (FXN) gene, encoding a mitochondrial protein involved in cellular iron homeostasis. The mutations (intronic repeat expansion) significantly reduce the expression of FXN	Iron dysregulation leading to progressive neuronal atrophy, mainly involving dorsal root ganglia and spinocerebellar tracts In the Lat, severe neuronal atrophy of glutamatergic projection neurons. PCs are also involved with disruption of synaptic terminals that connect with the Lat (grumose degeneration) [374]; Reduced thickness of retinal nerve fiber layer	Peripheral sensory neuropathy; progressive ataxia and motor disabilities	Fxn KO (Fxntm2.1Mkn) [375]; Rosa26-targeted Fxn1RNAi (Gt(ROSA)26Sortm1(H1/tetO-RNAi:Fxn)Dhg) [376]
Joubert syndrome [377–382]	Autosomal recessive disease. ~ 50% of cases are caused by mutations in genes that encode parts of primary cilia or basal bodies. Cilia sense morphogens like Wnt and Shh during development	Malformation of brainstem structures; cerebellar vermis hypoplasia, dysgenesis or agenesis of the cerebellar vermis; deep posterior interpeduncular fossa; thick and elongated superior cerebellar peduncles Malformation/faulty decussation of scp (molar tooth sign) Fragmentation of the Lat nucleus among other hindbrain changes; bilateral CN hypoplasia [378]	Congenital ataxia, hypotonia, episodic breathing dysregulation, mental retardation, and abnormal eye movements	JS3: Ahi-/- (Ahi1tm1Jgg) [383]; JS5: Cep290tm1.1Jgg [384]; JS7: Tmem67tm1Dgen, [385, 386]; JS17: Cplane1b2b012Clo [387]; JS26: KatnipGt(RRG309)Byg [388]; Arl13blox/lox(Arl13btm1.1Tc); NexCre(Neurod6tm1(cre)Kan)
Parkinson's disease (PD) [389–391]	Familial and non-familial forms	Degeneration of dopaminergic neurons of the substantia nigra pars compacta leading to dysfunction of striatopallidal circuits. PET results have highlighted a tremor-related network involving the Lat nuclei [391]	Tremor at rest, rigidity, bradykinesia, postural instability and non-motor signs (fatigue, depression, anxiety, dementia, autonomic dysfunction)	Neurotoxin-based approaches: 6-OHDA, MPTP, rotenone (pesticide), paraquat (herbicide), and maneb (fungicide). Chronic administration of neurotoxins induces models of progressive PD. Genetic or virally induced models are based on monogenic forms of PD, including SNCA, LRRK2, UCH-L1, PRKN, PINK1, and DJ-1, as well as manipulation of dopaminergic transcription factors [reviewed in 513]
Pontocerebellar hypoplasias, [393, 394]	A group of autosomal recessive neurodegenerative disorders; defects in tRNA splicing and other spliceosome or pre-mRNA complex cleavage genes	Spinal cord anterior horn cell degeneration Cerebellar hypoplasia and cerebellar and pons atrophy; neuronal loss in basal ganglia, gliosis in the brainstem, gliosis in the basal ganglia; scattered loss of PCs Segmental loss of Lat CN neurons while specific regions of the nucleus are preserved	Severe psychomotor delay and intellectual disability; uniformly fatal early in life	Ppil1em4Jgg, Ppil1em3Jgg, with a severely reduced cerebral and cerebellar size, [395]; Clp1em2Slac, displaying the loss of type 1B neurons in the Lat [396]