Abstract
The majority of patients affected with lysosomal storage disorders (LSD) exhibit neurological symptoms. For mucopolysaccharidosis type IIIC (MPSIIIC), the major burdens are progressive and severe neuropsychiatric problems and dementia, primarily thought to stem from neurodegeneration. Using the MPSIIIC mouse model, we studied whether clinical manifestations preceding massive neurodegeneration arise from synaptic dysfunction. Reduced levels or abnormal distribution of multiple synaptic proteins were revealed in cultured hippocampal and CA1 pyramidal MPSIIIC neurons. These defects were rescued by virus-mediated gene correction. Dendritic spines were reduced in pyramidal neurons of mouse models of MPSIIIC and other (Tay-Sachs, sialidosis) LSD as early as at P10. MPSIIIC neurons also presented alterations in frequency and amplitude of miniature excitatory and inhibitory postsynaptic currents, sparse synaptic vesicles, reduced postsynaptic densities, disorganized microtubule networks, and partially impaired axonal transport of synaptic proteins. Furthermore, postsynaptic densities were reduced in postmortem cortices of human MPS patients, suggesting that the pathology is a common hallmark for neurological LSD. Together, our results demonstrate that lysosomal storage defects cause early alterations in synaptic structure and abnormalities in neurotransmission originating from impaired synaptic vesicular transport, and they suggest that synaptic defects could be targeted to treat behavioral and cognitive defects in neurological LSD patients.
Highlights
Lysosomal storage diseases (LSD) are progressive, pediatric multisystemic disorders, with the typical cellular landmark of storage bodies, caused by lysosomal accumulation of undigested macromolecules
heparan sulfate (HS) colocalized with organelles positive for lysosomal-associated membrane protein 1 (LAMP1), while GM2 was only partially colocalized with LAMP1, suggesting that this ganglioside accumulated in nonlysosomal compartments
Our current data demonstrate that both excitatory and inhibitory synaptic inputs to the pyramidal CA1 hippocampal neurons are drastically reduced in the mouse model of Sanfilippo C syndrome already at P14–P20, at least 2–3 months before the development of other neuronal pathologies such as neuroinflammation, mitochondrial damage as well as neuronal accumulation of simple gangliosides and misfolded proteins [13]
Summary
Lysosomal storage diseases (LSD) are progressive, pediatric multisystemic disorders, with the typical cellular landmark of storage bodies, caused by lysosomal accumulation of undigested macromolecules. Neurological manifestations are common among mucopolysaccharidoses (MPS), which comprise approximately 30% of LSD cases [2]. Progressive and severe neurological decline is the major burden for mucopolysaccharidosis type III, known as Sanfilippo syndrome, a rare genetic neurogenerative disease manifesting with neuropsychiatric problems, such as hyperactivity, aggressiveness, and autistic features, followed by developmental delay, speech and hearing loss, and childhood dementia [3]. Survival may exceed the fourth decade of life [3], with progressive dementia and retinitis pigmentosa [4,5,6,7]. Four subtypes — A, B, C, and D — of the disease are associated with deficiencies of specific enzymes catalyzing subsequent steps of heparan sulfate (HS) catabolism [4, 5]: sulfamidase (MPSIIIA, OMIM 252900) [9], α-N-acetylglucosaminidase (MPSIIIB, OMIM 252920) [10], heparan acetyl CoA α-glucosaminide N-acetyltransferase or HGSNAT (MPSIIIC, OMIM 252930) [11], and N-acetylglucosamine-6-sulfatase (MPSIIID, OMIM 252940) [12]
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