Huntington's Disease and Neurogenesis

描述（由申请人提供）：亨廷顿舞蹈病（HD）是一种遗传性神经退行性疾病，可导致舞蹈病、痴呆和精神病，在美国影响约30,000人。HD的一种潜在治疗策略是通过刺激内源性神经元前体的增殖并将其迁移到受损的大脑区域来替代受伤或死亡的神经元。在HD患者大脑尾状核附近的室下区（SVZ）中，表达细胞增殖和未成熟神经元标记物的细胞数量增加。鉴于这一发现，并且由于生长因子在某些情况下具有神经保护作用，也可以刺激神经发生，我们用皮下成纤维细胞生长因子-2 （FGF-2）治疗HD转基因R6/2小鼠，发现FGF-2使野生型小鼠SVZ中溴脱氧尿苷（BrdU）标记的双皮质素（DCX）表达细胞的数量增加了30%，在HD转基因R6/2小鼠中增加了150%。FGF-2还诱导从SVZ向HD转基因R6/2小鼠的新纹状体和大脑皮层募集新神经元。在纹状体中，这些新神经元是表达darpp -32的细胞，具有中等棘神经元和苍白突起的特性，与HD丢失的神经元表型一致。FGF-2还能减少聚谷氨酰胺聚集，改善运动表现，延长寿命约20%。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a hereditary neurodegenerative disorder that produces choreoathetosis, dementia and psychosis and affects about 30,000 individuals in the United States. One potential treatment strategy for HD involves the replacement of injured or dead neurons by stimulating the proliferation of endogenous neuronal precursors and their migration into damaged brain regions. An increase in the number of cells that express cell-proliferation and immature neuronal markers has been observed in the subventricular zone (SVZ) adjacent to the caudate nucleus in brains of patients with HD. Given this finding, and because growth factors are neuroprotective in some settings and can also stimulate neurogenesis, we have treated HD transgenic R6/2 mice with subcutaneous fibroblast growth factor-2 (FGF-2), and found that FGF-2 increased the number of bromodeoxyuridine (BrdU)-labeled, doublecortin (DCX)-expressing cells in the SVZ by ~30% in wild-type mice, and by ~150% in HD transgenic R6/2 mice. FGF-2 also induced recruitment of new neurons from the SVZ into the neostriatum and cerebral cortex of HD transgenic R6/2 mice. In the striatum, these new neurons were DARPP-32-expressing cells with properties of medium spiny neurons and pallidal projections, consistent with the phenotype of neurons lost in HD. FGF-2 also reduced polyglutamine aggregates, improved motor performance, and extended lifespan by ~20%. We hypothesize that FGF-2, and perhaps other growth factors, can stimulate new neurons in the SVZ to proliferate, transit into striatum and cortex, develop functional properties of mature neurons, and integrate into brain circuitry to help offset HD-related deficits. We also hypothesize that functional outcome in HD will be improved by administration of neurogenesis-promoting factors. We will test these hypotheses with the following Specific Aims: (1) Determine the manner in which expression of expanded mutant human Htt in transgenic mice affects neuronal precursor cells in the adult SVZ with FGF-2 treatment. (2) Establish the migratory destinations and functional fate of newborn neurons in adult R6/2 HD-transgenic mice with FGF-2. (3) Examine the role of FGF-2-induced neurogenesis in ameliorating the transgenic HD phenotype. (4) Determine if other neurogenesis-promoting growth factors, or FGF-2 combined with other growth factors, improve the phenotype and survival of R6/2 HD transgenic mice to a greater extent than FGF-2 alone.We are developing a potential therapy to protect neurons or replace them in Huntington's disease.