Molecular pathogenesis of spinocerebellar ataxias

Abstract

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases, clinically and genetically heterogeneous, characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its afferent and efferent connections. Despite a well-described clinical and pathological phenotype, the molecular and cellular events that underlie neurodegeneration are still poorly understood. Compelling evidence points to major aetiological roles for interference with transcriptional regulation, protein aggregation and clearance, the ubiquitin-proteasome system and alterations of calcium homeostasis in the neuronal loss observed during the neurodegenerative process. But novel molecular routes that might be disrupted during disease progression are also being identified. These pathways could act independently or, more likely, interact and enhance each other, triggering the accumulation of cellular damage that eventually leads to dysfunction and, ultimately, the demise of neurons through a series of multiple events. This suggests that simultaneous targeting of several pathways might be therapeutically necessary to prevent neurodegeneration and preserve neuronal function. Understanding how dysregulation of these pathways mediates disease progression is leading to the establishment of effective therapeutic strategies in vivo, which may prove beneficial in the treatment of SCAs. Herein, we review the latest evidence for the proposed molecular processes to the pathogenesis of dominantly inherited spinocerebellar ataxias and the current therapeutic strategies.

Spinocerebellar ataxias

“…SCA type 3 is the most common form of the disease worldwide; types 1, 2, 6, 7 and 8 have greatly varying prevalences depending on the ethnic background of the population 1,2,[14][15][16][17][18][19] .…”

“…Other nervous system structures are usually affected, including the basal ganglia, brainstem nuclei, pyramidal tracts and posterior column and anterior horn of the spinal cord, as well as the peripheral nerves [1][2][3][4][5][6][7][8] .…”

“…SCAs are clinically characterized by the presence of cerebellar gait and limb ataxia (with dysmetria, dysdiadochokinesia, intention tremor, dysarthria and nystagmus), which may be accompanied by extracerebellar signs such as ophthalmoplegia, pyramidal signs, movement disorders (including parkinsonism, dystonia, myoclonia and chorea), dementia, epilepsy, visual disorders (including pigmentary retinopathy), lower motor neuron disease and peripheral neuropathy [1][2][3][4][5][6][7][8][9][10] .…”

Distribution of Transglutaminase 6 in the Central Nervous System of Adult Mice

“…The spinocerebellar ataxias (SCAs) are a large clinically and genetically heterogeneous group of inherited neurodegenerative disorders that are characterized by dysfunction of the cerebellum, as shown by progressive loss of balance and motor coordination of gait and limbs (Duenas et al, 2006). Atrophies of the cerebellum and brainstem are the prominent features, but different combinations of degeneration in the cerebellum, spinal tracts, peripheral nerves, cerebral cortex, basal ganglia, optic nerve, and others are also observed in SCA (Durr, 2010).…”

Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome

“…34,35 Mitochondria dysfunction at the cellular level and cerebellum involvement at the anatomic level are also related to other movement disorders such as dystonia and ataxia. 36,37 It is therefore plausible that an unbalanced mitochondria function through a defective cerebellar IMMP2L may contribute to tic formation. However, further studies are necessary to understand the involvement of mitochondria dysfunction due to a deficient IMMP2L in TS.…”