Dynactin is involved in Lewy body pathology

Abstract

Dynactin forms a protein complex with dynein that retrogradely transports cargo along microtubules. Dysfunction of this dynein-dynactin complex causes several neurodegenerative diseases such as Perry syndrome, motor neuron diseases and progressive supranuclear palsy. Recently, we reported colocalization of phosphorylated α-synuclein (p-SNCA) and the largest subunit of dynactin (DCTN1) in Lewy body (LB)-like structures in Perry syndrome. Previous reports have not focused on the relationship between dynactin and synucleinopathies. Thus, we examined autopsied human brains from patients with Parkinson's disease, dementia with LBs, and multiple system atrophy using immunohistochemistry for p-SNCA, DCTN1, dynactin 2 (DCTN2, dynamitin) and dynein cytoplasmic 1 intermediate chain 1 (DYNC1I1). We also examined microtubule affinity-regulating kinases (MARKs), which phosphorylate microtubule-associated proteins and trigger microtubule disruption. Both brainstem-type and cortical LBs were immunopositive for DCTN1, DCTN2, DYNC1I1 and p-MARK and their staining often overlapped with p-SNCA. Lewy neurites were also immunopositive for DCTN1, DCTN2 and DYNC1I1. However, p-SNCA-positive inclusions of multiple system atrophy, which included both glial and neuronal cytoplasmic inclusions, were immunonegative for DCTN1, DCTN2, DYNC1I1 and p-MARK. Thus, immunohistochemistry for dynein-dynactin complex molecules, especially DCTN1, can clearly distinguish LBs from neuronal cytoplasmic inclusions. Our results suggest that dynactin is closely associated with LB pathology.

Functional and molecular early enteric biomarkers for Parkinson’s disease in mice and men

“…Dynactin is part of a dynactin-dynein-complex (DDC), which is responsible for axonal transport and for the passage of cytoplasmic vesicles 77 . The DDC also affects α-synuclein aggregation, and dynactin dysregulation increases Lewy body formation in different brain regions 78 . In this study, we found reduced dynactin 2 expression in the MP of psA30P mice, suggesting for the first time that this decrease is associated with a reduced axonal transport of motor proteins in the gut at early stages of PD.…”

Parkinson Mice Show Functional and Molecular Changes in the Gut Long before Motoric Disease Onset

“…Dynactin is, as a part of the dynactin-dynein-complex (DDC), responsible for axonal transport, and the passage of cytoplasmic vesicles [82], and it affects α-synuclein aggregation increases Lewy body formation in different brain regions [83]. In this study, we found reduced dynactin 2 expression in the MP of psA30P mice, suggesting a reduced axonal transport of motor proteins in the gut at early stages of PD.…”

LRRK2-mediated phosphorylation of HDAC6 regulates HDAC6-cytoplasmic dynein interaction and aggresome formation

“…Several groups have linked HDAC6 to Lewy body formation and have shown that HDAC6 is a constituent of Lewy bodies 1,5,24 . A role for dynactin was also described in Lewy body formation 25 .…”