Cerebellar ataxias: β‐III spectrin's interactions suggest common pathogenic pathways

Abstract

Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of disorders all characterised by postural abnormalities, motor deficits and cerebellar degeneration. Animal and in vitro models have revealed β‐III spectrin, a cytoskeletal protein present throughout the soma and dendritic tree of cerebellar Purkinje cells, to be required for the maintenance of dendritic architecture and for the trafficking and/or stabilisation of several membrane proteins: ankyrin‐R, cell adhesion molecules, metabotropic glutamate receptor‐1 (mGluR1), voltage‐gated sodium channels (Nav) and glutamate transporters. This scaffold of interactions connects β‐III spectrin to a wide variety of proteins implicated in the pathology of many SCAs. Heterozygous mutations in the gene encoding β‐III spectrin (SPTBN2) underlie SCA type‐5 whereas homozygous mutations cause spectrin associated autosomal recessive ataxia type‐1 (SPARCA1), an infantile form of ataxia with cognitive impairment. Loss‐of β‐III spectrin function appears to underpin cerebellar dysfunction and degeneration in both diseases resulting in thinner dendrites, excessive dendritic protrusion with loss of planarity, reduced resurgent sodium currents and abnormal glutamatergic neurotransmission. The initial physiological consequences are a decrease in spontaneous activity and excessive excitation, likely to be offsetting each other, but eventually hyperexcitability gives rise to dark cell degeneration and reduced cerebellar output. Similar molecular mechanisms have been implicated for SCA1, 2, 3, 7, 13, 14, 19, 22, 27 and 28, highlighting alterations to intrinsic Purkinje cell activity, dendritic architecture and glutamatergic transmission as possible common mechanisms downstream of various loss‐of‐function primary genetic defects. A key question for future research is whether similar mechanisms underlie progressive cerebellar decline in normal ageing.

Critical roles of αII spectrin in brain development and epileptic encephalopathy

“…Also, βIII spectrin is reportedly present throughout the dendritic tree of cerebellar Purkinje cells, and is essential for the recruitment and maintenance of ankyrin-R at the plasma membrane. The loss of function of βIII spectrin results in thinner dendrites and excessive dendritic protrusions with loss of planarity, and leads to spinocerebellar ataxia type 5 (35,36). Taken together, the perturbation in ankyrin and β spectrin interactions in distinct neuronal domains underpins the pathogenesis of loss of function of αII spectrin, their universal binding partner (Figure 8).…”

The role of spectrin in cell adhesion and cell–cell contact

“…As it has been recently reported, the periodic, ruler-like membrane skeleton based on spectrin and actin serves as a nanoscale scaffold to mediate physical interactions between cell types of the neural stem cell lineage. 31 The cell-specific repertoire of spectrin subunits encoding gene defects underlies a new group of disorders, the neuronal spectrinopathies, which includes spectrin-associated autosomal recessive cerebellar ataxia type 1, 32,33 spinocerebellar ataxia type 5, 34,35 early infantile epileptic encephalopathy type 5, 36,37 West syndrome, 38 and serious cardiac disorders such as congenital arrhythmias, heart failure, and possibly sudden cardiac death. 39 In Drosophila, loss of b-spectrin has been reported to lead to the loss of Na þ /K þ -ATPase from the basolateral domain of epithelial cells.…”

A Patient Diagnosed with Spinocerebellar Ataxia Type 5 associated with SPTBN2: Case Repor

“…Spinocerebellar ataxias (SCAs) are a clinically heterogeneous group of autosomal dominant neurodegenerative disorders that cause cerebellar ataxia by disrupting the afferent and efferent pathways of the cerebellum 1) . The typical age of onset is between the 30s and 40s, and presentation can be with different clinical symptoms.…”