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Role of the Metabolic Homeostasis-ISR Axis in C9orf72-ALS/FTD

Award Number: R01NS146192
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Role of the Metabolic Homeostasis-ISR Axis in C9orf72-ALS/FTD - The GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene (C9-HRE) is the most common genetic cause of ALS and FTD. Yet, the proximal biochemical triggers that link this repeat expansion to neurodegeneration remain unresolved. PET scan studies revealed early brain glucose hypometabolism in presymptomatic C9-HRE carriers, and human post-mortem CNS tissue analysis consistently shows activation of the integrated stress response (ISR). Our recent work demonstrated that metabolic rewiring precedes overt pathology in a C9-ALS/FTD BAC mouse model, and that neuronal glucose hypometabolic stress activates GCN2, the ISR kinase responsive to uncharged tRNAs. Notably, pharmacological inhibition of GCN2 or attenuation of the ISR with ISRIB reduces the synthesis of dipeptide repeat proteins (DPRs) produced by non- AUG-initiated, repeat-associated translation (RAN-T) of C9-HRE transcripts, underscoring the therapeutic promise of targeting this pathway. In parallel, our preliminary findings indicate that DPR production promotes the formation of ribosome dimers (disomes), suggesting that ribosome collisions may trigger ISR activation. There is, therefore, sufficient evidence to suggest the existence of a feed-forward mechanism in which ISR activation enhances DPR synthesis, and the resulting accumulation of DPRs further amplifies ISR signaling. Here, we propose to test the hypothesis that C9-ALS/FTD follows a self-amplifying pathogenic cascade in which (i) metabolic stress → (ii) uncharged tRNAs and ribosome stalling → (iii) GCN2 activation/ISR stress → (iv) enhanced RAN translation and DPR burden → (v) further metabolic/ISR stress. Testing this central hypothesis will be carried out in three aims: Aim 1 defines the temporal sequence of metabolic rewiring, ribosome stress, and ISR activation in the AAV- G4C2149 mouse model using 13C-glucose flux, mitochondrial assays, neuropathological analysis, and behavioral assessment; Aim 2 establishes how DPR synthesis induces ribosome collisions and activates GCN2 using patient-derived neurons, disome profiling, tRNA-seq, and DPR-ribosome co-sedimentation assays; Aim 3 tests whether genetic ablation of GCN2 restores metabolic homeostasis, reduces DPR and C9-ALS/FTD-related pathology, and improves functional outcomes in mice and human iPSC-derived cerebral organoid models, with validation in post-mortem C9-ALS/FTD CNS tissues. Our objective is to define how metabolic dysfunction and ribosome-mediated ISR activation drive disease progression in C9-ALS/FTD and to determine whether interrupting the GCN2-ISR pathway restores metabolic homeostasis. By elucidating and therapeutically targeting this maladaptive circuit, the proposed studies have the potential to establish a unifying disease mechanism and pave the way for ISR-directed therapies in C9-ALS/FTD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $653,174 )
2026	2026	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/26/2026	NEW	$653,174
														Subtotal = $653,174

Grand Total All Awards = $653,174

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Role of the Metabolic Homeostasis-ISR Axis in C9orf72-ALS/FTD

Award Number: R01NS146192

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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