Dendritic spine loss and neurodegeneration is rescued by Rab11 in models of Huntington's disease

Abstract

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by expansion of a polyglutamine tract in the huntingtin protein (htt) that mediates formation of intracellular protein aggregates. In the brains of HD patients and HD transgenic mice, accumulation of protein aggregates has been causally linked to lesions in axo-dendritic and synaptic compartments. Here we show that dendritic spines -sites of synaptogenesis -are lost in the proximity of htt aggregates because of functional defects in local endosomal recycling mediated by the Rab11 protein. Impaired exit from recycling endosomes (RE) and association of endocytosed protein with intracellular structures containing htt aggregates was demonstrated in cultured hippocampal neurons cells expressing a mutant htt fragment. Dendrites in hippocampal neurons became dystrophic around enlarged amphisome-like structures positive for Rab11, LC3 and mutant htt aggregates. Furthermore, Rab11 overexpression rescues neurodegeneration and dramatically extends lifespan in a Drosophila model of HD. Our findings are consistent with the model that mutant htt aggregation increases local autophagic activity, thereby sequestering Rab11 and diverting spine-forming cargo from RE into enlarged amphisomes. This mechanism may contribute to the toxicity caused by protein misfolding found in a number of neurodegenerative diseases.

The autophagic roles of Rab small GTPases and their upstream regulators

“…It was previously shown that RAB11 is required for the fusion of autophagosomes with multivesicular bodies (MVBs). [44][45][46] These studies reported that depletion of RAB11 results in the decreased convergence of RAB11-decorated MVBs with LC3-labeled autophagosomes. Furthermore, this role of RAB11 may be affected by the toxic aggregates of the HTT/huntingtin protein during Huntington disease (HD), which can lead to neurodegeneration.…”

“…112 Several studies showed that RAB11 dysfunction or loss of its activity underlies the cellular pathomechanism of HD [113][114][115] and in various HD models, RAB11 is able to rescue the neuronal loss. 46,116 Besides RAB11, RAB8 is also involved in HD and its mislocalization results in perturbation of post-Golgi trafficking to lysosomes 117 that may affect autophagic degradation. Dysregulation of the autophagic process is found in HD as well.…”

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

“…Therefore, we used a Drosophila model of HD, in which flies pan-neuronally express a mutant HTT exon 1 fragment (HTT93Q) and exhibit a progressive loss of photoreceptor neurons (rhabdomeres) during their lifespan. [34][35][36][37][38] Treatment of adult HD flies with either mometasone or GRT10 markedly rescued mutant HTT-mediated neurodegeneration, although the extent of protection with GRT10 was slightly lower than with mometasone (Figures 3c and d). Moreover, treatment of the glucocorticoids during larval stages reduced neurodegeneration in newly emerged (day 0) HD flies (Figure 3e), suggesting that the transrepression arm of glucocorticoid signaling is neuroprotective both in adult HD flies and during development.…”

The long and the short of aberrant ciliogenesis in Huntington disease

“…Mutant Htt expression disrupts both Rab8 and Rab11 activity by affecting normal localization of Rab8 on Golgi membranes (20) and by impairing guanine nucleotide exchange factor activity on Rab11, resulting in reduced recycling of cargo proteins (21). Expression of a constitutively active form of Rab11 in primary neurons from an HD mouse model ameliorates deficits in extracellular cysteine uptake by restoring cell surface levels of the glutamate transporter EAAC1 (22), and overexpression of Rab11 in a Drosophila model of HD rescues neurodegeneration and extends lifespan (23). Thus, it is possible that manipulating the activity and expression levels of HAP1, dynein, Rab8, and Rab11 might ameliorate at least some aspects of ciliary dysfunction in HD.…”