Novel destabilizing Dynactin variant (DCTN1 p.Tyr78His) in patient with Perry syndrome

Čierny, Marek; Hooshmand, Sam; Fee, Dominic B.; Tripathi, Swarnendu; Dsouza, Nikita R.; Kirschner, Alison La Pean; Zimmermann, Michael T.; Brennan, Ryan

doi:10.1016/j.parkreldis.2020.06.006

Cited by 8 publications

(1 citation statement)

References 11 publications

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“…On the other hand, Perry disease is an autosomal dominant, fatal neurodegenerative disease characterized clinically by early-onset parkinsonism, depression/apathy, weight loss and central hypoventilation; and pathologically by degeneration of substantia nigral dopaminergic neurons and TDP-43 proteinopathy [ 45 , 46 , 47 , 48 , 49 , 50 ]. Eleven missense, Perry disease-linked mutations in DCTN1 (e.g., p.G71A) have been identified so far ( Figure 1 A) [ 49 , 51 ]. Although these DCTN1 mutants exhibit impairments of CAP-Gly domain function, such as microtubule-binding and retrograde transport initiation [ 13 , 14 , 44 , 47 ], pathological mechanisms that distinctly cause Perry disease or HMN7B are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

DCTN1 Binds to TDP-43 and Regulates TDP-43 Aggregation

Deshimaru

Kinoshita-Kawada

Kubota

et al. 2021

IJMS

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A common pathological hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis, is cytoplasmic mislocalization and aggregation of nuclear RNA-binding protein TDP-43. Perry disease, which displays inherited atypical parkinsonism, is a type of TDP-43 proteinopathy. The causative gene DCTN1 encodes the largest subunit of the dynactin complex. Dynactin associates with the microtubule-based motor cytoplasmic dynein and is required for dynein-mediated long-distance retrograde transport. Perry disease-linked missense mutations (e.g., p.G71A) reside within the CAP-Gly domain and impair the microtubule-binding abilities of DCTN1. However, molecular mechanisms by which such DCTN1 mutations cause TDP-43 proteinopathy remain unclear. We found that DCTN1 bound to TDP-43. Biochemical analysis using a panel of truncated mutants revealed that the DCTN1 CAP-Gly-basic supradomain, dynactin domain, and C-terminal region interacted with TDP-43, preferentially through its C-terminal region. Remarkably, the p.G71A mutation affected the TDP-43-interacting ability of DCTN1. Overexpression of DCTN1G71A, the dynactin-domain fragment, or C-terminal fragment, but not the CAP-Gly-basic fragment, induced cytoplasmic mislocalization and aggregation of TDP-43, suggesting functional modularity among TDP-43-interacting domains of DCTN1. We thus identified DCTN1 as a new player in TDP-43 cytoplasmic-nuclear transport, and showed that dysregulation of DCTN1-TDP-43 interactions triggers mislocalization and aggregation of TDP-43, thus providing insights into the pathological mechanisms of Perry disease and other TDP-43 proteinopathies.

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