Rab GTPase Expression Changes in α-Synucleinopathy and Tauopathy Disorders

Congratulations to Mayur ParmarGina BaeNathaniel MaShivang Jadvani, and Nikolaus McFarland on the publication of “Rab GTPase Expression Changes in α-Synucleinopathy and Tauopathy Disorders,” in the April 9th edition of Neurology.



Objective: Determine Rab GTPase expression changes in α-synucleinopathy and tauopathy disorders.

Background: Alterations in Rab GTPase function are increasingly implicated in neurodegenerative disease pathology. In Lewy body disorders, Rab proteins interact with α-synuclein and several are substrates of PINK1 and LRRK2 kinases, supporting a potential role in Parkinson disease (PD). Expression of specific Rabs (e.g., Rab1, 3a, 8a) rescues α-synuclein associated trafficking deficits, vesicle accumulation, and toxicity. Rab proteins have similarly been linked to tau disorders such as Alzheimer disease (AD). However, little is known about the role of Rab GTPases in other tau disorders and expression patterns in neurodegenerative disease.

Design/Methods: We examined expression levels of several Rab GTPase proteins (Rab 3a, 5, 7, 8a, 10, 11a, and 35) in postmortem human brain samples from multiple tauopathy (AD, PSP, CBD), Lewy body (α-synucleinopathy) disorders (PD, DLB, MSA), and matched controls. Tissues from select brain regions including frontal and temporal cortex, striatum, cerebellum, and white matter were analyzed. Frozen brain samples were homogenized in high salt buffer and analyzed by Western blot with specific Rab antibodies.

Results: Rab3a expression was significantly increased in the striatum of DLB and MSA, but not PD. Rab8a levels were decreased in frontal and temporal cortex in atypical parkinsonian disorders (APD) compared to control. Rab11a was similarly decreased in frontal cortex in APD’s, but increased in the striatum and white matter of PSP and CBD. Rab35, recently implicated as potential PD biomarker, appeared unchanged in PD but was significantly decreased in the striatum in APD’s.

Conclusions: These findings represent the first comprehensive analysis of Rab GTPase expression in neuropathological tissues and demonstrate differential expression patterns for Rab proteins in disease-affected regions of tau and α-synuclein disorders. Further studies are needed to determine the potential impact and role of Rab proteins in neurodegenerative disease pathology.