Myotonic Dystrophy: an RNA Toxic Gain of Function Tauopathy?

Abstract

Myotonic dystrophies (DM) are rare inherited neuromuscular disorders linked to microsatellite unstable expansions in non-coding regions of ubiquitously expressed genes. The DMPK and ZNF9/CNBP genes which mutations are responsible for DM1 and DM2 respectively. DM are multisystemic disorders with brain affection and cognitive deficits. Brain lesions consisting of neurofibrillary tangles are often observed in DM1 and DM2 brain. Neurofibrillary tangles (NFT) made of aggregates of hyper and abnormally phosphorylated isoforms of Tau proteins are neuropathological lesions common to more than 20 neurological disorders globally referred to as Tauopathies. Although NFT are observed in DM1 and DM2 brain, the question of whether DM1 and DM2 are Tauopathies remains a matter of debate. In the present review, several pathophysiological processes including, missplicing, nucleocytoplasmic transport disruption, RAN translation which are common mechanisms implicated in neurodegenerative diseases will be described. Together, these processes including the missplicing of Tau are providing evidence that DM1 and DM2 are not solely muscular diseases but that their brain affection component share many similarities with Tauopathies and other neurodegenerative diseases. Understanding DM1 and DM2 pathophysiology is therefore valuable to more globally understand other neurodegenerative diseases such as Tauopathies but also frontotemporal lobar neurodegeneration and amyotrophic lateral sclerosis.