Consensus paper: pathological mechanisms underlying neurodegeneration in spinocerebellar ataxias

Abstract

Intensive scientific research devoted in the recent years to understand the molecular mechanisms or neurodegeneration in spinocerebellar ataxias (SCAs) are identifying new pathways and targets providing new insights and a better understanding of the molecular pathogenesis in these diseases. In this consensus manuscript, the authors discuss their current views on the identified molecular processes causing or modulating the neurodegenerative phenotype in spinocerebellar ataxias with the common opinion of translating the new knowledge acquired into candidate targets for therapy. The following topics are discussed: transcription dysregulation, protein aggregation, autophagy, ion channels, the role of mitochondria, RNA toxicity, modulators of neurodegeneration and current therapeutic approaches. Overall point of consensus includes the common vision of neurodegeneration in SCAs as a multifactorial, progressive and reversible process, at least in early stages. Specific points of consensus include the role of the dysregulation of protein folding, transcription, bioenergetics, calcium handling and eventual cell death with apoptotic features of neurons during SCA disease progression. Unresolved questions include how the dysregulation of these pathways triggers the onset of symptoms and mediates disease progression since this understanding may allow effective treatments of SCAs within the window of reversibility to prevent early neuronal damage. Common opinions also include the need for clinical detection of early neuronal dysfunction, for more basic research to decipher the early neurodegenerative process in SCAs in order to give rise to new concepts for treatment strategies and for the translation of the results to preclinical studies and, thereafter, in clinical practice.

Fig. 1

Most common molecular pathways identified triggering neurodegeneration in the SCAs. DCD dark cell degeneration (SCA2, SCA3, SCA7, SCA28). 1 Aggregation (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA17, SCA35, DRPLA). 2 Caspase activation (SCA1, SCA2, SCA3. SCA6, SCA7, SCA8, SCA12, SCA17, DRPLA). 3 Autophagy (SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, DRPLA). 4 Ca²⁺ homeostasis/signaling alterations (SCA1, SCA2, SCA6, SCA14, SCA15, SCA16). 5 Disruption of axonal transport and vesicle trafficking (SCA5, SCA11, SCA27). 6 Glutamate excitotoxicity (SCA1, SCA2, SCA3, SCA6, SCA12). 7 Interference with transcription (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, DRPLA). 8 Mitochondrial impairment (SCA1, SCA2, SCA3, SCA6, SCA17, SCA8, SCA17, SCA28, DRPLA). 9 Oxidative stress (SCA2, SCA3, SCA7, SCA12). 10 Alterations of proteasome degradation (SCA1, SCA3, SCA5, SCA7, SCA14). 11 Early synaptic neurotransmission deficits (SCA1, SCA2, SCA3, SCA5, SCA6, SCA7, SCA8, SCA14, SCA17, SCA31, DRPLA). 12 Unfolded protein response (UPR) (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA17, DRPLA). 13 Potassium channel dysfunction (SCA13, SCA19/22). 14 Tau phosphorylation dysregulation (SCA11). 15 Neuronal membrane skeleton defects (SCA5). 16 Neurite alterations (SCA1, SCA10, SCA14). 17 Voltage-gated Na⁺ channel dysregulation (SCA27). 18 Proteostatic disruption (SCA26). 19 Protein phosphatase 2A (PP2A) activity dysregulation (SCA1, SCA2, SCA12). 20 Protein kinase C (PKC) activity deficits (SCA1, SCA14).

Fig. 2

Toxic RNA species and their effects. Non-coding microsatellite expansions, such as the ATTCT expansion in SCA10, are transcribed, but not translated. The RNA form foci which bind and sequester RNA binding proteins (RBPs). Sequestration of the RBP is hypothesized to alter the normal function of RBP and have deleterious downstream effects on RNA splicing, translational regulation, apoptosis and autophagy, in addition to other uncharacterized and unknown effects. Coding microsatellite expansions have long been recognised as a protein gain of function producing polyglutamine-containing proteins. However, their gene loci can also serve as a substrate for bidirectional transcription. The natural sense and antisense transcripts may then be used in RAN translation.