Abstract
Krabbe's disease (KD) is primarily a demyelinating disorder, but recent studies have identified the presence of neuronal protein aggregates in the brain, at least partially composed by alpha-synuclein (α-syn). The role of this protein aggregation in the pathogenesis of KD is largely unknown, but it has added KD to a growing list of lysosomal storage diseases that can be also be considered as proteinopathies. While the presence of these protein aggregates within the KD brain is now appreciated, the remainder of the central nervous system (CNS) remains uncharacterized. This study is the first to report the presence of thioflavin-S reactive inclusions throughout the spinal cord of both murine and human spinal tissue. Stereological analysis revealed the temporal and spatial accumulation of these inclusions within the neurons of the ventral spinal cord vs. those located in the dorsal cord. This study also confirmed that these thio-S positive accumulations are present within neuronal populations and are made up at least in part by α-syn in both the twitcher mouse and cord autopsied material from affected human patients. Significantly, neonatal gene therapy for galactosylceramidase, a treatment that strongly improves the survival and health of KD mice, but not bone marrow transplantation prevents the formation of these inclusions in spinal neurons. These results expand the understanding of α-syn protein aggregation within the CNS of individuals afflicted with KD and underlines the tractability of this problem via early gene therapy, with potential impact to other synucleinopathies such as PD.
Highlights
Krabbe’s disease (KD) is a lysosomal sphingolipidosis caused by mutations in the galactosylceramidase gene (GALC) (Suzuki and Suzuki, 1971) leading to accumulation of the neurotoxic lipid galactosylsphingosine (Svennerholm et al, 1980; Igisu and Suzuki, 1984)
Based on our studies showing α-syn accumulations in the twitcher brain (Smith et al, 2014) and their positive response to associated virus (AAV)-based gene therapy (Abdelkarim et al, 2018), here we investigated the hypothesis that the entire central nervous system (CNS) and the spinal cords of twitcher and human Krabbe patients are impacted by neuronal protein aggregates, and are responsive to gene therapy correction of GALC deficiency
To investigate the spatial and temporal accumulation of protein aggregates that may be present in the spinal cord, sections from the cervical and lumbar levels of the cord from twitcher mice were stained for the presence of thioflavin-S positive inclusions
Summary
Krabbe’s disease (KD) is a lysosomal sphingolipidosis caused by mutations in the galactosylceramidase gene (GALC) (Suzuki and Suzuki, 1971) leading to accumulation of the neurotoxic lipid galactosylsphingosine (or psychosine) (Svennerholm et al, 1980; Igisu and Suzuki, 1984). Protein aggregates of α-syn are a pathological hallmark of certain adult-onset neurodegenerative diseases such as Parkinson’s disease (PD) (Spillantini et al, 1997) and have been identified in other lysosomal storage disorders, most notably Gaucher’s disease (GD) (Shachar et al, 2011; Xu et al, 2011) Dysfunction in psychosine metabolism caused by GALC mutations has been suggested as a risk factor for PD (Marshall and Bongarzone, 2016; Marshall et al, 2018a)
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