Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
Neurodegener Dis. 2009;6(5-6):219-20. doi: 10.1159/000258704. Epub 2010 Feb 10.
Frontotemporal lobar degeneration with TAR-DNA-binding protein inclusions (FTLD-TDP) is the most common pathological subtype of frontotemporal dementia (FTD). Mutations leading to a loss of function in the progranulin gene (PGRN) are the most common known cause of FTLD-TDP. In agreement with the proposed loss of function disease mechanism, several groups have reported decreased plasma levels of PGRN in patients carrying PGRN mutations compared to individuals without PGRN mutations. We propose that traumatic brain injury (TBI), an environmental factor, may also increase the risk of FTD by altering PGRN metabolism. TBI may lead to an increase in the central nervous system levels of microglial elastases, which proteolyze PGRN into proinflammatory products called granulins causing a reduction in PGRN levels. Hence, inhibiting microglial activation may have an important implication for the prevention of FTD in patients with TBI.
额颞叶痴呆（FTD）伴 TAR-DNA 结合蛋白包涵体（FTLD-TDP）是额颞叶痴呆（FTD）最常见的病理亚型。导致颗粒蛋白前体基因（PGRN）功能丧失的突变是 FTLD-TDP 最常见的已知病因。与提出的功能丧失疾病机制一致，有几个研究组报告称，与没有 PGRN 突变的个体相比，携带 PGRN 突变的患者的血浆 PGRN 水平降低。我们提出，创伤性脑损伤（TBI）作为一种环境因素，也可能通过改变 PGRN 代谢而增加 FTD 的风险。TBI 可能导致中枢神经系统中微胶质弹性蛋白酶水平升高，从而将 PGRN 蛋白水解为促炎产物颗粒素，导致 PGRN 水平降低。因此，抑制小胶质细胞激活可能对预防 TBI 患者的 FTD 具有重要意义。
