Karyopherin α-3 is a key protein in the pathogenesis of spinocerebellar ataxia type 3 controlling the nuclear localization of ataxin-3

Abstract

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a CAG expansion in the gene leading to a polyglutamine expansion in the ataxin-3 protein. The nuclear presence and aggregation of expanded ataxin-3 are critical steps in disease pathogenesis. To identify novel therapeutic targets, we investigated the nucleocytoplasmic transport system by screening a collection of importins and exportins that potentially modulate this nuclear localization. Using cell,, and mouse models, we focused on three transport proteins, namely, CRM1, IPO13, KPNA3, and their respective orthologs Emb, Cdm, and Kap-α3. While overexpression of CRM1/Emb demonstrated positive effects in, KPNA3/Kap-α3 emerged as the most promising target, as knockdown via multiple RNAi lines demonstrated its ability to shuttle both truncated and full-length expanded ataxin-3, rescue neurodegeneration, restore photoreceptor formation, and reduce aggregation. Furthermore, knockout in SCA3 mice resulted in an amelioration of molecular and behavioral disturbances such as total activity, anxiety, and gait. Since KPNA3 is known to function as an import protein and recognize nuclear localization signals (NLSs), this work unites ataxin-3 structure to the nuclear pore machinery and provides a link between karyopherins, NLS signals, and polyglutamine disease, as well as demonstrates that KPNA3 is a key player in the pathogenesis of SCA3.

Physiological and pathophysiological characteristics of ataxin-3 isoforms

“…3C). This is especially important, as we previously observed that ataxin-3's toxicity is linked to its nuclear localization (29,30).…”

“…Ataxin-3 was reported to be located in different compartments of the cell (3,4,46). Moreover, the nucleus was previously reported to be an essential site for MJD pathology (29,30). We therefore asked whether ataxin-3 isoforms differ in their subcellular localization.…”

“…Cleavage is required for aggregate formation in vitro and in vivo and may be part of the pathogenesis according to the toxic fragment hypothesis (28). Moreover, the nuclear localization of ataxin-3 turned out to be critical for the manifestation of MJD (29,30). The exact pathogenic mechanisms of MJD, however, are still not understood in depth, but it is known that the expanded polyQ repeat induces dysfunctions in the cell via different mechanisms.…”

Nucleus–cytoplasm cross‐talk in the aging brain

“…Defects in nuclear import play a causative role in the pathogenesis of ALS/FTD (Boeynaems, Bogaert, Van Damme, & Van Den Bosch, ; Kim and Taylor, ) and polyQ diseases similar to HD such as spinocerebellar ataxia type 3 (SCA3) (Sowa et al, ). While in some cases overexpression of importins was shown to be beneficial and neuroprotective (Guo et al, ; Jovičić et al, ), in other cases, depletion of importins rescued neurodegeneration (Sowa et al, ). The pathogenic mechanisms at the bases of the different diseases are still to be fully elucidated, and so the potential pharmacological intervention.…”

Dynamics of Ischemia-Dependence as Neurodegeneration

“…The nuclear presence and aggregation of expanded ataxin-3 are critical in pathogenesis of spinocerebellar ataxia type 3 with linkage to the nuclear pore machinery [3]. Neuroinflammation and the presence of amyloid beta protein and neurofibrillary tangles are critical lesions in Alzheimer's disease [4].…”