Atrophin‐1 Function and Dysfunction in Dentatorubral–Pallidoluysian Atrophy

Abstract

Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, incurable genetic disease that belongs to the group of polyglutamine (polyQ) diseases. DRPLA is the most common in the Japanese population; however, its global prevalence is also increasing due to better clinical recognition. It is characterized by cerebellar ataxia, myoclonus, epilepsy, dementia, and chorea. DRPLA is caused by dynamic mutation of CAG repeat expansion in ATN1 gene encoding the atrophin-1 protein. In the cascade of molecular disturbances, the pathological form of atrophin-1 is the initial factor, which has not been precisely characterized so far. Reports indicate that DRPLA is associated with disrupted protein-protein interactions (in which an expanded polyQ tract plays a crucial role), as well as gene expression deregulation. There is a great need to design efficient therapy that would address the underlying neurodegenerative process and thus prevent or alleviate DRPLA symptoms. An in-depth understanding of the normal atrophin-1 function and mutant atrophin-1 dysfunction is crucial for this purpose.

Establishing resources and increasing awareness to advance research on Dentatorubral-pallidoluysian atrophy toward a treatment: a patient organization perspective

“…The function of the gene product, atrophin-1, is imperfectly understood, though it is thought to act as a transcriptional co-repressor. 5 However, the abnormally long CAG repeat expansion changes the structure of atrophin-1, rendering it capable of aggregation. This altered protein accumulates in neurons, ultimately interfering with normal cell functions.…”