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Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation.

ABSTRACT: Loss-of-function mutations in GRN cause frontotemporal dementia (FTD) with transactive response DNA-binding protein of 43 kD (TDP-43)-positive inclusions and neuronal ceroid lipofuscinosis (NCL). There are no disease-modifying therapies for either FTD or NCL, in part because of a poor understanding of how mutations in genes such as GRN contribute to disease pathogenesis and neurodegeneration. By studying mice lacking progranulin (PGRN), the protein encoded by GRN, we discovered multiple lines of evidence that PGRN deficiency results in impairment of autophagy, a key cellular degradation pathway. PGRN-deficient mice are sensitive to Listeria monocytogenes because of deficits in xenophagy, a specialized form of autophagy that mediates clearance of intracellular pathogens. Cells lacking PGRN display reduced autophagic flux, and pathological forms of TDP-43 typically cleared by autophagy accumulate more rapidly in PGRN-deficient neurons. Our findings implicate autophagy as a novel therapeutic target for GRN-associated NCL and FTD and highlight the emerging theme of defective autophagy in the broader FTD/amyotrophic lateral sclerosis spectrum of neurodegenerative disease.

SUBMITTER: Chang MC

PROVIDER: S-EPMC5584112 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation.

Chang Michael C MC Srinivasan Karpagam K Friedman Brad A BA Suto Eric E Modrusan Zora Z Lee Wyne P WP Kaminker Joshua S JS Hansen David V DV Sheng Morgan M

The Journal of experimental medicine 20170804 9

Loss-of-function mutations in GRN cause frontotemporal dementia (FTD) with transactive response DNA-binding protein of 43 kD (TDP-43)-positive inclusions and neuronal ceroid lipofuscinosis (NCL). There are no disease-modifying therapies for either FTD or NCL, in part because of a poor understanding of how mutations in genes such as GRN contribute to disease pathogenesis and neurodegeneration. By studying mice lacking progranulin (PGRN), the protein encoded by GRN, we discove ...[more]

PMID: 28778989

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Project description:Loss-of-function mutations in the multifunctional growth factor progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) with TDP-43 protein accumulation. Nuclear TDP-43 protein with key roles in RNA metabolism is also aggregated in amyotrophic lateral sclerosis (ALS), suggesting that ALS and FTLD constitute a broad disease continuum. However, the fact that mutations in GRN are associated with FTLD, while mutations in TDP-43 cause a preferential loss of motor neurons resulting in ALS-end of the disease spectrum, suggests involvement of both cell-autonomous and non-autonomous mechanisms. Studies on animal models and in vitro studies have been instrumental in understanding the link between GRN and TDP-43 and also their role in neurodegeneration. For instance, in mouse models, allelic deficiencies of Grn do not recapitulate human pathology of TDP-43 brain accumulations, but embryonic neurons derived from these mice do show abnormal TDP-43 accumulation after additional cellular challenges, suggesting that TDP-43 changes observed in GRN mutation carriers might also relate to stress. Recent results have shown that the dual action of GRN in growth modulation and inflammation could be due to its negative regulation of TNF-α signaling. In addition, GRN also interacts with sortilin and is endocytosed, thereby regulating its own levels and possibly also modulating the turnover of other proteins including that of TDP-43. Accumulating evidence suggests that TDP-43 abnormal cellular aggregation causes a possible gain of function, also suggested by recently constructed mouse models of TDP-43 proteinopathy; however, it would be inconvincible that sequestration of physiological TDP-43 within cellular aggregates observed in patients would be innocuous for disease pathogenesis. This review discusses some of these data on the possible link between GRN and TDP-43 as well as mechanisms involved in TDP-43-led neurodegeneration. Continued multitiered efforts on genetic, cell biological, and animal modeling approaches would prove crucial in finding a cure for GRN-related diseases.

Dataset Information

Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation.

Publications

Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation.

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