A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons

Abstract

The molecular motor dynein and its associated regulatory subunit dynactin have been implicated in several neurodegenerative conditions of the basal ganglia, such as Huntington's disease (HD) and Perry syndrome, an atypical Parkinson-like disease. This pathogenic role has been largely postulated from the existence of mutations in the dynactin subunit p150(Glued). However, dynactin is also able to act independently of dynein, and there is currently no direct evidence linking dynein to basal ganglia degeneration. To provide such evidence, we used here a mouse strain carrying a point mutation in the dynein heavy chain gene that impairs retrograde axonal transport. These mice exhibited motor and behavioural abnormalities including hindlimb clasping, early muscle weakness, incoordination and hyperactivity. In vivo brain imaging using magnetic resonance imaging showed striatal atrophy and lateral ventricle enlargement. In the striatum, altered dopamine signalling, decreased dopamine D1 and D2 receptor binding in positron emission tomography SCAN and prominent astrocytosis were observed, although there was no neuronal loss either in the striatum or substantia nigra. In vitro, dynein mutant striatal neurons displayed strongly impaired neuritic morphology. Altogether, these findings provide a direct genetic evidence for the requirement of dynein for the morphology and function of striatal neurons. Our study supports a role for dynein dysfunction in the pathogenesis of neurodegenerative disorders of the basal ganglia, such as Perry syndrome and HD.

Sustained Systemic Glucocerebrosidase Inhibition Induces Brain α-Synuclein Aggregation, Microglia and Complement C1q Activation in Mice

“…Moreover, transgenic mice with a point mutation in the dynein heavy chain gene will also impair retrograde axonal transport and cause motor and behavioral abnormalities including hindlimb clasping, loss of muscle tone, and incoordination, which is accompanied by striatal atrophy and dystrophic neurites (5). These studies support a role for dynactin and dynein in the pathogenesis of neurodegenerative disorders.…”

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

“…The deficit in axonal transport includes mitochondria [64]. Finally, a point mutation in the dynein heavy chain leads to prominent striatal neurodegeneration, implying that MSNs are particularly sensitive to deficits in retrograde axonal transport [65]. Axonal transport has not been studied in regional HD models.…”

Alteration of Motor Protein Expression Involved in Bidirectional Transport in Peripheral Blood Mononuclear Cells of Patients with Amyotrophic Lateral Sclerosis

“…Although very useful, they do not always reflect the clinical and pathological changes present in human subjects [37,38,40]. Many papers indicated that disorders in the intracellular transport might be crucial for the initiation or progression of motor neuron degeneration [35,41,42,43,44]. In our previous studies, we observed important changes in the expression of tau isoforms, kinesins and dynactin in various regions of the CNS obtained from autopsies of SALS patients and transgenic mice with symptoms of motor neuron degeneration [36,37,38,45].…”