Neurogenesis has recently been observed in the adult human brain, suggesting the possibility of endogenous neural repair. However, the augmentation of neurogenesis in the adult human brain in response to neuronal cell loss has not been demonstrated. This study was undertaken to investigate whether neurogenesis occurs in the subependymal layer (SEL) adjacent to the caudate nucleus in the human brain in response to neurodegeneration of the caudate nucleus in Huntington's disease (HD). Postmortem control and HD human brain tissue were examined by using the cell cycle marker proliferating cell nuclear antigen (PCNA), the neuronal marker βIII-tubulin, and the glial cell marker glial fibrillary acidic protein (GFAP). We observed a significant increase in cell proliferation in the SEL in HD compared with control brains. Within the HD group, the degree of cell proliferation increased with pathological severity and increasing CAG repeats in the HD gene. Most importantly, PCNA ⁺ cells were shown to coexpress βIII-tubulin or GFAP, demonstrating the generation of neurons and glial cells in the SEL of the diseased human brain. Our results provide evidence of increased progenitor cell proliferation and neurogenesis in the diseased adult human brain and further indicate the regenerative potential of the human brain.

Computer-supported gait analysis has proven to be effective for the comprehensive assessment of gait changes in rodent models of neurodegenerative and neurological disorders. However, full characterization of individual gait parameters is required for specific neurological or neurodegenerative disorders such as Parkinson's disease (PD). Gait disturbances in particular present as the most constraining set of symptoms in PD, finally depriving patients from most activities of normal daily living. In this study, we have characterized the gait pattern abnormalities observed in two rat models of PD: the medial forebrain bundle (MFB) 6-OHDA lesion model and the striatal 6-OHDA lesion model. Our data indicates significant changes in 21 different gait parameters in the MFB lesion cohort. We observed a steady decline in the overall walking speed and cadence, as well as significant alterations in the gait parameters stride length, initial dual stance, paw print position, step cycle, swing phase of the step cycle, stand index, phase dispersion, print length, and print area in at least one of the paws. These alterations correlated with the extent of tyrosine hydroxylase (TH) neuronal loss observed in this group. These alterations were detected as early as 1 week post lesion. In contrast, limited gait dysfunction was detected in the striatal lesion cohort related to the low level of TH neuronal loss detected in this group. In this study we have demonstrated that gait analysis is a reliable method for the detection of motor deficiencies in a MFB 6-OHDA lesion model of PD and may prove a clinically relevant, low impact method of testing functional impairment as early as 1 week post lesion.

Two decades ago, researchers identified that a CAG expansion mutation in the huntingtin (HTT) gene was involved in the pathogenesis of Huntington's disease (HD). However, since the identification of the HTT gene, there has been no advance in the development of therapeutic strategies to prevent or reduce the progression of HD. With the recent advances in stem cell biology and human cell reprogramming technologies, several novel and exciting pathways have emerged allowing researchers to enhance their understanding of the pathogenesis of HD, to identify and screen potential drug targets, and to explore alternative donor cell sources for cell replacement therapy. This review will discuss the role of compensatory neurogenesis in the HD brain, the use of stem cell-based therapies for HD to replace or prevent cell loss, and the recent advance of cell reprogramming to model and/or treat HD. These new technologies, coupled with advances in genome editing herald a promising new era for HD research with the potential to identify a therapeutic strategy to alleviate this debilitating disorder. Stem Cells 2017