Mutant Huntingtin Impairs BDNF Release from Astrocytes by Disrupting Conversion of Rab3a-GTP into Rab3a-GDP

Abstract

Brain-derived neurotrophic factor (BDNF) is essential for neuronal differentiation and survival. We know that BDNF levels decline in the brains of patients with Huntington's disease (HD), a neurodegenerative disease caused by the expression of mutant huntingtin protein (mHtt), and furthermore that administration of BDNF in HD mice is protective against HD neuropathology. BDNF is produced in neurons, but astrocytes are also an important source of BDNF in the brain. Nonetheless, whether mHtt affects astrocytic BDNF in the HD brain remains unknown. Here we investigated astrocytes from HD140Q knock-in mice and uncovered evidence that mHtt decreases BDNF secretion from astrocytes, which is mediated by exocytosis in astrocytes. Our results demonstrate that mHtt associates with Rab3a, a small GTPase localized on membranes of dense-core vesicles, and prevents GTP-Rab3a from binding to Rab3-GAP1, disrupting the conversion of GTP-Rab3a into GDP-Rab3a and thus impairing the docking of BDNF vesicles on plasma membranes of astrocytes. Importantly, overexpression of Rab3a rescues impaired BDNF vesicle docking and secretion from HD astrocytes. Moreover, ATP release and the number of ATP-containing dense-core vesicles docking are decreased in HD astrocytes, suggesting that the exocytosis of densecore vesicles is impaired by mHtt in HD astrocytes. Further, Rab3a overexpression reduces reactive astrocytes in the striatum of HD140Q knock-in mice. Our results indicate that compromised exocytosis of BDNF in HD astrocytes contributes to the decreased BDNF levels in HD brains and underscores the importance of improving glial function in the treatment of HD.

Unravelling and Exploiting Astrocyte Dysfunction in Huntington’s Disease

“…Expression of mHTT in astrocytes resulted in death of co-cultured striatal neurons [29], and expression of a mHTT N-terminal fragment with either 98 or 160Qs in astrocytes in vivo using the human GFAP promoter lead to reduced GLT1 expression, astrogliosis, and HD-like pathology [9, 38, 39]. Loss of BDNF release from astrocytes has also been reported [40]. Behavioural alterations and premature death were observed in the hGFAP-Q160 expressing model [38, 41].…”

Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease

“…Astrocytes in AD are reactive at early stages, have impaired Ca 2ϩ signaling, regulate ␤-amyloid burden, and influence synaptic plasticity alterations also contributing to excitotoxicity (Acosta et al, 2017). Interestingly, astrocytes normally express the BDNF protein, although at lesser levels than neurons (Saha et al, 2006;Giralt et al, 2010;Fulmer et al, 2014;Hong et al, 2016). Therefore, engineered astrocytes could be good candidates to release neurotrophic factors.…”

Overview of Huntington's Disease Models: Neuropathological, Molecular, and Behavioral Differences

“…In the Q111 model, BDNF vesicular transport is disrupted in cortical neurons (Pineda et al., ). In Q140 mice, the deficient transport is mediated by interaction of mutant HTT with proteins involved in the docking of BDNF vesicles in astrocytes (Hong, Zhao, Li, & Li, ). In addition, BDNF expression is downregulated in the cortex and striatum at 12 months of age in both heterozygous and homozygous Q175 mice (Ma, Yang, Li, Milner, & Hempstead, ).…”