Traumatic brain injury may increase the risk for frontotemporal dementia through reduced progranulin.
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.
Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. alijawaid84@gmail.com
Ali
A
Jawaid
Rosa
R
Rademakers
Joseph S
JS
Kass
Yogeshwar
Y
Kalkonde
Paul E
PE
Schulz
D001930:Brain Injuries / Q000150:complications* / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000209:etiology* / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000077153:Progranulins; D012307:Risk Factors
D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins