Failure to Thrive: Impaired BDNF Transport along the Cortical–Striatal Axis in Mouse Q140 Neurons of Huntington’s Disease

Abstract

Boosting trophic support to striatal neurons by increasing levels of brain-derived neurotrophic factor (BDNF) has been considered as a target for therapeutic intervention for several neurodegenerative diseases, including Huntington’s disease (HD). To aid in the implementation of such a strategy, a thorough understanding of BDNF cortical–striatal transport is critical to help guide its strategic delivery. In this manuscript, we investigate the dynamic behavior of BDNF transport along the cortical–striatal axis in Q140 primary neurons, a mouse model for HD. We examine this by using single-molecule labeling of BDNF conjugated with quantum dots (QD-BDNF) to follow the transport along the cortical–striatal axis in a microfluidic chamber system specifically designed for the co-culture of cortical and striatal primary neurons. Using this approach, we observe a defect of QD-BDNF transport in Q140 neurons. Our study demonstrates that QD-BDNF transport along the cortical–striatal axis involves the impairment of anterograde transport within axons of cortical neurons, and of retrograde transport within dendrites of striatal neurons. One prominent feature we observe is the extended pause time of QD-BDNF retrograde transport within Q140 striatal dendrites. Taken together, these finding support the hypothesis that delinquent spatiotemporal trophic support of BDNF to striatal neurons, driven by impaired transport, may contribute to the pathogenesis of HD, providing us with insight into how a BDNF supplementation therapeutic strategy may best be applied for HD.

Brain-Derived Neurotrophic Factor Dysregulation as an Essential Pathological Feature in Huntington’s Disease: Mechanisms and Potential Therapeutics

“…Indeed, mouse primary neuron models that employ the lentiviral transduction of mHTT exon 1 display the downregulation of Bdnf gene expression well before decrements in measures of viability [ 104 , 105 ]. Untransfected primary neurons harvested from embryonic-age HD mouse models also displayed aberrations in BDNF expression, transport, or release in culture [ 106 , 107 , 108 ]. More innovative approaches, including induced pluripotent stem cells (iPSCs) and the direct reprogramming of fibroblasts obtained from HD patients, are increasingly used to model HD [ 109 ].…”

“…Although no significant evidence exists to support the specific disruption of trafficking of the Bdnf transcript in HD, we note that others have shown that BDNF and its transcripts are co-segregated in neurons [ 161 ]. Therefore, reports of altered BDNF protein distribution and transportation across degrading trafficking networks within HD neurons may be equally applicable to its transcript [ 79 , 108 , 118 ].…”

Genetically engineered neural stem cells (NSCs) therapy for neurological diseases; state‐of‐the‐art

“…219 BDNF activities are bargained in HD, probably since the mHTT impairs its cortico-striatal transport, thus causing striatal neurodegeneration. 220,221 Wild-type HTT adjusts BDNF transport and indirectly improves the BDNF genetic expression, while BDNF overexpression brings about phenotypic recovery in a rodent model of HD. 222 Recently, iPSCs-derived NSCs therapy decreased behavioral dysfunctions and ameliorated neuropathological alterations in the YAC128 mouse model of HD in part by elevating BDNF and TrkB levels in striata of treated mice.…”

“…Further, given that BDNF is a critical neurotrophic factor for the cortico‐striatal synaptic activity and the survival of GABAergic neurons, therapeutic effects of BDNF‐overexpressing human NSCs (BDNF‐HB1.F3) has been assessed in HD rat model 219 . BDNF activities are bargained in HD, probably since the mHTT impairs its cortico‐striatal transport, thus causing striatal neurodegeneration 220,221 . Wild‐type HTT adjusts BDNF transport and indirectly improves the BDNF genetic expression, while BDNF overexpression brings about phenotypic recovery in a rodent model of HD 222 .…”