Progranulin is Neurotrophic In Vivo and Protects against a Mutant TDP-43 Induced Axonopathy

Mislocalization, aberrant processing and aggregation of TAR DNA-binding protein 43 (TDP-43) is found in the neurons affected by two related diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal lobe dementia (FTLD). These TDP-43 abnormalities are seen when TDP-43 is mutated, such as in familial ALS, but also in FTLD, caused by null mutations in the progranulin gene. They are also found in many patients with sporadic ALS and FTLD, conditions in which only wild type TDP-43 is present. The common pathological hallmarks and symptomatic cross over between the two diseases suggest that TDP-43 and progranulin may be mechanistically linked. In this study we aimed to address this link by establishing whether overexpression of mutant TDP-43 or knock-down of progranulin in zebrafish embryos results in motor neuron phenotypes and whether human progranulin is neuroprotective against such phenotypes. Mutant TDP-43 (A315T mutation) induced a motor axonopathy characterized by short axonal outgrowth and aberrant branching, similar, but more severe, than that induced by mutant SOD1. Knockdown of the two zebrafish progranulin genes, grna and grnb, produced a substantial decrease in axonal length, with knockdown of grna alone producing a greater decrease in axonal length than grnb. Progranulin overexpression rescued the axonopathy induced by progranulin knockdown. Interestingly, progranulin also rescued the mutant TDP-43 induced axonopathy, whilst it failed to affect the mutant SOD1-induced phenotype. TDP-43 was found to be nuclear in all conditions described. The findings described here demonstrate that progranulin is neuroprotective in vivo and may have therapeutic potential for at least some forms of motor neuron degeneration

Progranulin and C9orf72 in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

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Differentially expressed genes in Alzheimer’s disease highlighting the roles of microglia genes including OLR1 and astrocyte gene CDK2AP1

Background: Alzheimer’s disease (AD) is associated with abnormal tau and amyloid-β accumulation in the brain, leading to neurofibrillary tangles, neuropil threads and extracellular amyloid-β plaques. Treatment is limited to symptom management, a disease-modifying therapy is not available. To advance search of therapy approaches, there is a continued need to identify targets for disease intervention both by confirming existing hypotheses and generating new hypotheses. Methods: We conducted a mRNA-seq study to identify genes associated with AD in post-mortem brain samples from the superior temporal gyrus (STG, n ​= ​76), and inferior frontal gyrus (IFG, n ​= ​65) brain regions. Differentially expressed genes (DEGs) were identified correcting for gender and surrogate variables to capture hidden variation not accounted for by pre-planned covariates. The results from this study were compared with the transcriptome studies from the Accelerated Medicine Partnership – Alzheimer’s Disease (AMP-AD) initiative. Over-representation and gene set enrichment analysis (GSEA) was used to identify disease-associated pathways. Protein-protein interaction (PPI) and weighted gene co-expression network analysis (WGCNA) analyses were carried out and co-expressed gene modules and their hub genes were identified and associated with additional phenotypic traits of interest. Results: Several hundred mRNAs were differentially expressed between AD cases and cognitively normal controls in the STG, while no and few transcripts met the same criteria (adjusted p less than 0.05 and fold change greater than 1.2) in the IFG. The findings were consistent at the gene set level with two out of three cohorts from AMP-AD. PPI analysis suggested that the DEGs were enriched in protein-protein interactions than expected by random chance. Over-representation and GSEA analysis suggested genes playing roles in neuroinflammation, amyloid-β, autophagy and trafficking being important for the AD disease process. At the gene level, 10 genes from the STG that were consistently differentially expressed in this study and in the MSBB study (one of the three cohorts within the AMP-AD initiative) were enriched in microglial genes (TREM2, C3AR1, ITGAX, OLR1, CD74, and HLA-DRA), but also included genes with a broader cell type expression pattern such as CDK2AP1. Among the DEGs with supporting evidence from an independent study, CDK2AP1 (most abundantly expressed in astrocyte) was the transcript with strongest association with antemortem cognitive measure (last Mini-Mental State Examination score) and neurofibril tangle burden but also associated with amyloid plaque burden, while OLR1 was the transcript with strongest association with amyloid plaque burden. GSEA and over-representation analyses revealed gene sets related to immune processes including neutrophil degranulation, interleukin 10 signaling, and interferon gamma signaling, complement and coagulation cascades, phosphatidylinositol signaling system, phagosome and neurotransmitter receptors and postsynaptic signal transmission were enriched from this study and replicated in an independent study. Conclusion: This study identified differential gene sets, common with two out of three AMP-AD cohorts (ROSMAP and MSBB) and highlights microglia and astrocyte as the key cell-types with DGEs associated with AD clinical diagnosis, and/or antemortem cognitive measure as well as neuropathological indices. Future meta-analysis and causal inferential analysis will be helpful in pinpointing the most relevant pathways and genes to intervene

Progranulin does not affect motor neuron degeneration in mutant SOD1 mice and rats

Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is familial in 10% of patients, with mutations in SOD1 and C9orf72 being the most frequent cause. There is convincing evidence for overlap between ALS and frontotemporal lobar degeneration at the genetic, pathological, and clinical level. Null mutations in progranulin (PGRN) are a frequent cause of familial frontotemporal lobar degeneration. PGRN exerts neurotrophic properties on motor neurons in vitro and in vivo. We therefore examined whether PGRN could affect disease progression in mutant SOD1 mice and rats, both established models for ALS. Overexpression of PGRN in mice and intracerebroventricular delivery of PGRN in rats did not affect onset or progression of motor neuron degeneration.status: publishe

The neurotrophic properties of progranulin depend on the granulin E domain but do not require sortilin binding

Progranulin (PGRN) is a growth factor involved in wound healing, inflammation, tumor growth, and neurodegeneration. Mutations in the gene encoding PGRN give rise to shortage of PGRN and cause familial frontotemporal lobar degeneration. PGRN exerts neurotrophic functions and binding of PGRN to the membrane receptor sortilin (SORT1) mediates the endocytosis of PGRN. SORT1-mediated uptake plays an important role in the regulation of extracellular PGRN levels. We studied the role of SORT1 in PGRN-mediated neuroprotection in vitro and in vivo. The survival-enhancing effect of PGRN seemed to be dependent on the granulin E (GRN E) domain. Pharmacologic inhibition of the GRN E-SORT1 interaction or deletion of the SORT1 binding site of GRN E did not abolish its neurotrophic function. In addition, the in vivo phenotype of PGRN knockdown in zebrafish embryos was not phenocopied by SORT1 knockdown. These results suggest that GRN E mediates the neurotrophic properties of PGRN and that binding to SORT1 is not required for this effect.status: publishe