Tuesday, January 14, 2025
1/14/2025
Frontotemporal dementia (FTD) represents 10 to 20% of all dementia cases. GRN mutations account for up to 20 percent of familial and 5 percent of sporadic FTD. Homozygous GRN mutations cause the rare lysosomal storage disease ceroid lipofuscinosis. Dysfunctional lysosomal degradation pathways due to reduced granulin function can lead to TDP-43 proteinopathy. TDP-43 has been implicated in regulating transcription, alternative splicing, and mRNA stability. GRN-FTD manifests as the behavioral variant (bvFTD), primary progressive aphasia, and movement disorders with extrapyramidal features such as parkinsonism and corticobasal syndrome. It is unknown what brain circuits cause motor symptoms and aphasia in GRN-FTD patients. Basal ganglia are involved in both motor and language functions. It is unknown whether and how GRN mutation affects basal ganglia, leading to motor symptoms and aphasia. We obtained a line of Grn (mouse homolog of human GRN) knockin (KI) mice with the most common GRN-FTD mutation found in human patients. Preliminary studies of Grn KI mice showed earlier onset motor coordination and balance deficits, accompanied by altered firing patterns of striatal neurons. Our long-term goal is to use mouse models to elucidate the pathophysiology of motor symptoms and language deficits associated with FTD. The specific objective of this proposal is to determine the effect of Grn knockout restricted to the striatum on motor and non-motor symptoms in mice. We hypothesize that heterozygous striatum-specific loss of function of the progranulin protein leads to TDP-43 proteinopathy and reduced hyperpolarization-activated cyclic nucleotide-gated (HCN) mRNA and protein expression, in turn results in motor and communication deficits accompanied by anatomical and functional deficits in the basal ganglia, especially in the striatal cholinergic interneurons (ChIs) and medium spiny neurons (MSNs). The rationale for the proposed research is that once the mechanisms of the altered striatal neurons and motor and aphasia symptoms in FTD are clarified, novel therapeutics can be developed to treat motor and non-motor symptoms in FTD patients. We plan to test our hypothesis with the following Specific Aims: Aim 1: To test the hypothesis that the heterozygous striatum-specific Grn knockout mice have deficits both in motor and non-motor behaviors, we will examine the mutant mice with a behavioral test battery. Aim 2: To test the hypothesis that altered striatal neurons in the heterozygous striatum-specific Grn knockout mice contribute to motor and non-motor symptoms in FTD, we will a) quantify the number of striatal ChIs by immunohistochemistry, b) analyze the in vitro activity and morphology of striatal neurons, and c) quantify proteins involved in striatal cholinergic metabolism and HCN expression. The successful completion of the above aims will allow us to determine how the altered properties of striatal neurons can lead to motor dysfunction and aphasia in FTD. Characterizing these neurons will provide novel targets for treatment and offer great promise for developing targeted therapies for motor dysfunction and aphasia associated with FTD.
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