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Understanding the Role of BLOC1S1 in Myelin Development

Award Number: R21NS147239
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: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Understanding the Role of BLOC1S1 in Myelin Development - ABSTRACT BLOC1S1-related leukoencephalopathy (BLOC1S1-LE) is a rare neurological condition characterized by hypomyelination, epilepsy, and global developmental delays. BLOC1S1 is a shared subunit of the Biogenesis of Lysosomal Organelles Complex-1(BLOC1) and BLOC-One-Related Complex (BORC) that govern various endo- lysosomal (LYS) pathways. BORC mediates kinesin-dependent transport of LYS toward autophagosomes (with Arl8-SKIP-kinesin) and conducts homotypic fusion and protein sorting (HOPS)-supported autophagosome-LYS and endosome-LYS fusion. Although several subunits of BORC result in severe myelin deficits, how BORC causes myelin deficits remains unclear. This proposal aims to uncover how the BORC-HOPS complex dysregulates autophagy and affects the differentiation of oligodendrocyte precursor cells (OPCs) to oligodendrocytes (OLs; myelin-producing cells). To address this, we will use conditional mouse models targeting OPCs and assess whether Bloc1s1 depletion disrupts the BORC-HOPS- N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) ensemble, henceforth disrupting the autophagosome-LYS fusion and dysregulating autophagy. We will also generate OPC and OL-like cells from patient-derived iPSC of BLOC1S1- LE and replicate these findings (Aim 1). As OLs are the sole producers of myelin in the central nervous system, we will conditionally delete Bloc1s1 in OLs and assess the transport of myelin proteins and cholesterol, essential components for myelin formation. We will also evaluate if alterations in BORC disrupt LYS biogenesis and transport of key myelin components (Aim 2). To confirm the functional relation of LYS deficits to BLOC1S1-loss, we will attempt to rescue OL lineages with a lentiviral construct of BLOC1S1 in murine and iPSC-derived OPC and OLs. This proposal will address a gap in knowledge on how LYS function and vesicle homeostasis are essential for myelin formation.


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 = $489,500 )
2026	2026	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/28/2026	NEW	$489,500
														Subtotal = $489,500

Grand Total All Awards = $489,500

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Understanding the Role of BLOC1S1 in Myelin Development

Award Number: R21NS147239

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: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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