BDNF Overexpression in the Forebrain Rescues Huntington's Disease Phenotypes in YAC128 Mice

Abstract

Huntington's disease (HD) is caused by an expansion of the polyglutamine tract at the N terminus of huntingtin. This mutation reduces levels of BDNF in the striatum, likely by inhibiting cortical Bdnf gene expression and anterograde transport of BDNF from the cerebral cortex to the striatum. Substantial evidence suggests that this reduction of striatal BDNF plays a crucial role in HD pathogenesis. Here we report that overexpression of BDNF in the forebrain rescues many disease phenotypes in YAC128 mice that express a full-length human huntingtin mutant with a 128-glutamine tract. The Bdnf transgene, under the control of the promoter for ␣ subunit of Ca 2ϩ /calmodulindependent protein kinase II, greatly increased BDNF levels in the cerebral cortex and striatum. BDNF overexpression in YAC128 mice prevented loss and atrophy of striatal neurons and motor dysfunction, normalized expression of the striatal dopamine receptor D2 and enkephalin, and improved procedural learning. Furthermore, quantitative analyses of Golgi-impregnated neurons revealed a decreased spine density and abnormal spine morphology in striatal neurons of YAC128 mice, which was also reversed by increasing BDNF levels in the striatum. These results demonstrate that reduced striatal BDNF plays a crucial role in the HD pathogenesis and suggest that attempts to restore striatal BDNF level may have therapeutic effects to the disease.

Dendritic Spine Instability Leads to Progressive Neocortical Spine Loss in a Mouse Model of Huntington's Disease

“…It is likely that mutant huntingtin, by disrupting vesicular trafficking of BDNF, influences spine survival on cortical neurons. Interestingly, overexpression of BDNF has been shown to rescue defective synaptic plasticity and related mechanisms in animal models of HD (Lynch et al, 2007;Xie et al, 2010).…”

“…Interestingly, the mRNA and protein levels of PSD-95 and AMPA receptors are reduced in HD patients and in animal models (Cha et al, 1998;Sun et al, 2001;Luthi-Carter et al, 2003). Maintenance and stabilization of dendritic spines are regulated by synaptic activity, as well as by the molecular complex at the postsynaptic density of spines, consisting of neurotransmitter receptors, scaffolding proteins (PSD-95), enzymes, and cytoskeletal proteins (Yoshihara et al, 2009). Close correlation exists between spine head size, PSD size, AMPA receptor number, and spine stability; a phenomenon that possibly shows similarities to LTP (Yoshihara et al, 2009).…”

“…In many neurodegenerative conditions, such as in tauopathies, alterations in synapses and dendritic spines are some of the earliest manifestations of the disease (Yoshiyama et al, 2007). The HD mouse model, R6/2, is an excellent model to study progressive early synaptic dysfunctions, because this model mimics the cognitive as well as motor phenotype of HD in the absence of any clear neuronal loss.…”

Micro RNA -214,-150,-146a and-125b targetHuntingtingene

“…28 Exogenous overexpression of BDNF rescues HD phenotypes in YAC 128 mice. 29 We checked whether the expression of BDNF is altered in STHdh Q111 /Hdh Q111 cells and if there are any effects of miRNAs targeting HTT gene on the expression of BDNF. BDNF expression was decreased in STHdh Q111 /Hdh Q111 cells compared to that of in STHdh Q7 /Hdh Q7 cells (Fig.…”

Machado-Joseph Disease / Spinocerebellar Ataxia Type 3

“…Many research groups have investigated the use of neurotrophic factors for therapy of polyglutamine disorders over the last decade (Bensadoun et al, 2000;de Almeida et al, 2001;Zala et al, 2004;Xie et al, 2010). In HD the BDNF supply to striatal neurons is compromised.…”