Work

PT581. Multiple accumulation of neurodegenerative disease-related proteins in familial granulin mutation brains

Year: 2016

Type: conference-abstract

Abstract: Granulin (GRN) mutations were identified in patients with familial frontotemporal lobar degeneration (FTLD) with ubiquitin pathology in 2006 studies. GRN transcript haploinsufficiency has been proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. GRN mutations were first found in tau-negative FTLD patients, however, recent findings indicate that these mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer’s disease and corticobasal degeneration. Moreover, PGRN reduction in tau transgenic mice is associated with increasing tau phosphorylation and accumulation. To investigate the influence of a decline in PGRN protein on other forms of neurodegenerative-related protein accumulation, four human GRN mutation cases (age at death; 54, 55, 56 and 78 years old) were investigated by histochemical and biochemical analyses. The results showed neuronal and glial tau accumulation in all cases analyzed. Massive neuronal tau staining revealed pretangle forms and glial tau in both astrocytes and oligodendrocytes. Furthermore, phosphorylated α-synuclein-positive structures were also found in oligodendrocytes and the neuropil. Immunoblot analysis of fresh frozen brain tissues revealed that tau protein was present in the sarkosyl-insoluble fraction, which was composed of three- and four-repeat tau isoforms, resembling Alzheimer’s disease. Our data suggest that PGRN reduction might be the cause of neuronoglial multiple proteinopathies, including TDP-43 proteinopathy, tauopathy and α-synucleinopathy, due to the accelerating accumulation of abnormal proteins.

Source: The International Journal of Neuropsychopharmacology

DOI: 10.1093/ijnp/pyw044.581