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Brain-Specific Vulnerability to Ubiquitous ASPM Loss in Microcephaly

Award Number: R21NS153438
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: 09/05/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Brain-Specific Vulnerability to Ubiquitous ASPM Loss in Microcephaly - SUMMARY/ABSTRACT Primary microcephaly presents a fundamental question in developmental biology: mutations in ubiquitously expressed genes cause severe, brain-speciﬁc growth deﬁcits while sparing other highly proliferative organs. For example, ASPM (abnormal spindle-like microcephaly-associated) encodes a centrosomal protein essential for cell proliferation throughout the body and is the most common cause of autosomal recessive microcephaly when mutated. Yet, loss of ASPM results in profound reductions in brain size and intellectual disability without affecting body stature or the structure of tissues like the kidney or intestine. Despite its clinical importance, the molecular mechanisms conferring this “brain-speciﬁc vulnerability” remain unknown, largely because prior research has not directly compared the molecular consequences of ASPM loss across affected and unaffected tissues. To bridge this gap, we utilize a unique Aspm knockout (KO) ferret model. While Aspm KO mice exhibit mild phenotypes, our Aspm KO ferrets faithfully recapitulate the severe human disease features—including a 25–40% reduction in cortical volume, premature progenitor delamination, and robust cell death—while maintaining normal body size. Our CENTRAL HYPOTHESIS is that cortical progenitors possess an “intrinsic vulnerability” driven by cortex-speciﬁc ASPM interactions that are absent in somatic tissues. To test the hypothesis, we propose two Speciﬁc Aims. Aim 1 will deﬁne the cellular and transcriptomic basis of this vulnerability: 1A) quantify proliferation and cell death across four ASPM-expressing tissues (cortex, lung, kidney, and intestine) in embryonic ferrets; and 1B) employ Seq-Scope—a high-resolution spatial transcriptomics technology—to map progenitor-speciﬁc stress responses in situ. Aim 2 will identify the molecular mediators of this vulnerability: 2A) perform antibody- directed proximity labeling to deﬁne the in situ ASPM interactome; and 2B) parallel centrosome afﬁnity capture to proﬁle centrosome composition across the same four tissues in WT and KO ferrets. Our research will elucidate why loss of the ubiquitous protein ASPM causes brain-speciﬁc microcephaly, identifying novel therapeutic targets for neurodevelopmental disorders of cortical progenitors. Moreover, our methods and conceptual framework may advance the understanding of other neurological disorders where the loss of ubiquitously expressed genes causes tissue-restricted pathogenesis.


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 = $462,950 )
2026	2026	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/3/2026	NEW	$462,950
														Subtotal = $462,950

Grand Total All Awards = $462,950

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Brain-Specific Vulnerability to Ubiquitous ASPM Loss in Microcephaly

Award Number: R21NS153438

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: 09/05/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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