Distal spinal and bulbar muscular atrophy caused by dynactin mutation

Abstract

Impaired axonal transport has been postulated to play a role in the pathophysiology of multiple neurodegenerative disorders. In this report, we describe the results of clinical and neuropathological studies in a family with an inherited form of motor neuron disease caused by mutation in the p150 Glued subunit of dynactin, a microtubule motor protein essential for retrograde axonal transport. Affected family members had a distinct clinical phenotype characterized by early bilateral vocal fold paralysis affecting the adductor and abductor laryngeal muscles. They later experienced weakness and atrophy in the face, hands, and distal legs. The extremity involvement was greater in the hands than in the legs, and it had a particular predilection for the thenar muscles. No clinical or electrophysiological sensory abnormality existed; however, skin biopsy results showed morphological abnormalities of epidermal nerve fibers. An autopsy study of one patient showed motor neuron degeneration and axonal loss in the ventral horn of the spinal cord and hypoglossal nucleus of the medulla. Immunohistochemistry showed abnormal inclusions of dynactin and dynein in motor neurons. This mutation of dynactin, a ubiquitously expressed protein, causes a unique pattern of motor neuron degeneration that is associated with the accumulation of dynein and dynactin in neuronal inclusions.

The G59S Mutation in p150gluedCauses Dysfunction of Dynactin in Mice

“…The most distinct clinical phenotype of patients carrying the G59S mutation in p150 glued is early bilateral vocal fold paralysis that affects the abductor and abductor laryngeal muscles (Puls et al, 2005). Muscle weakness and atrophy in the face, hands, and distal legs were observed later, reflecting motor neuron degeneration in the ventral horn of the spinal cord and hypoglossal nucleus of the medulla.…”

“…Wild-type and Dctn1 ϩ/m mice showed no significant differences in performance in either the accelerating rotarod or grip strength at 10 and 16 months of age (data not shown). Because older patients carrying the G59S mutation in p150 glued had steppage gait (Puls et al, 2005), and SOD1 G93A mice, a well established mouse model for ALS, developed significantly shorter stride length (Gurney et al, 1994;Puttaparthi et al, 2002;Puls et al, 2005), we examined the gait of Dctn1 ϩ/m mice using the Treadscan Gait Analysis system. We quantified the stride length of wild-type and Dctn1 ϩ/m mice at 4 and 16 months of age.…”

Atomic-resolution structure of the CAP-Gly domain of dynactin on polymeric microtubules determined by magic angle spinning NMR spectroscopy

“…Specifically, point mutations in the CAP-Gly domain of the p150 Glued subunit of the dynactin complex (the structure of the complex is shown in Fig. 1), which binds to MTs and the associated protein EB1, have been described in patients with Perry syndrome, distal spinal bulbar muscular atrophy, and amyotrophic lateral sclerosis (ALS) (3)(4)(5)(6). Mutations in the cargo-binding domain and other regions of the dynein-dynactin motor complex lead to developmental defects and neurological diseases, such as ALS, Charcot-Marie-Tooth disease, and Huntington's disease (7)(8)(9)(10).…”

Internal Dynamics of Dynactin CAP-Gly Is Regulated by Microtubules and Plus End Tracking Protein EB1

“…CAPGly domains are conserved in eukaryotes and constitute, in addition to dynactin, a number of other microtubule-associated proteins (8). Mutations in the CAP-Gly domain are associated with various neurological disorders, such as distal spinal bulbar muscular atrophy (9,10) and Perry syndrome (11). Despite biochemical and structural studies by us and by others, the underpinnings by which the CAP-Gly mutations are related to neurological disorders remain poorly understood.…”