Haploinsufficiency of lysosomal enzyme genes in Alzheimer’s disease
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Abstract
There is growing evidence suggesting that the lysosome or lysosome dysfunction is associated with Alzheimer’s disease (AD). Pathway analysis of post mortem brain-derived proteomic data from AD patients shows that the lysosomal system is perturbed relative to similarly aged unaffected controls. However, it is unclear if these changes contributed to the pathogenesis or are a response to the disease. Consistent with the hypothesis that lysosome dysfunction contributes to AD pathogenesis, whole genome sequencing data indicate that heterozygous pathogenic mutations and predicted protein-damaging variants in multiple lysosomal enzyme genes are enriched in AD patients compared to matched controls. Heterozygous loss-of-function mutations in the palmitoyl protein thioesterase-1 ( PPT1 ), α-L-iduronidase ( IDUA ), β-glucuronidase ( GUSB ), N-acetylglucosaminidase ( NAGLU ), and galactocerebrosidase ( GALC ) genes have a gene-dosage effect on Aβ 40 levels in brain interstitial fluid in C57BL/6 mice and significantly increase Aβ plaque formation in the 5xFAD mouse model of AD, thus providing in vivo validation of the human genetic data. A more detailed analysis of PPT1 heterozygosity in 18-month-old mice revealed changes in α-, β-, and γ-secretases that favor an amyloidogenic pathway. Proteomic changes in brain tissue from aged PPT1 heterozygous sheep are consistent with both the mouse data and the potential activation of AD pathways. Finally, CNS-directed, AAV-mediated gene therapy significantly decreased Aβ plaques, increased life span, and improved behavioral performance in 5xFAD/PPT1+/- mice. Collectively, these data strongly suggest that heterozygosity of multiple lysosomal enzyme genes represent risk factors for AD and may identify precise therapeutic targets for a subset of genetically-defined AD patients.
Significance Statement
Lysosomes play a role in the degradation of aggregation-prone proteins such as amyloid β (Aβ). Homozygous lysosomal enzyme gene defects result in fatal pediatric lysosomal storage diseases and, historically, carriers were considered normal. However, a human genetic analysis identified deleterious heterozygous variants in multiple lysosomal enzyme genes that are enriched in Alzheimer’s disease (AD) patients. Those findings were validated in vivo by demonstrating that heterozygous loss-of-function (LoF) mutations in five different lysosomal enzyme genes affect Aβ processing and exacerbate Aβ plaque formation. CNS-directed gene therapy ameliorated the effects of a heterozygous LoF mutation in one of those genes in a mouse model of AD. These findings provide insights into the role of lysosomes in AD and have important therapeutic implications.
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Coronal sections of the brains from seven-month-old 5xFAD/PPT1+/- mice were analyzed for amyloid plaque burden using anti-amyloid antibodies (HJ3.4). There is an obvious (Fig. 1C) and statistically significant increase (Fig. 1D) in Aβ plaques in the 5xFAD/PPT1+/- mice compared to the parental 5xFAD strain.
This is very striking data! I'm curious if you looked, or if you know, whether the PPT1 heterozygous mice (the black line in figure 1B) have plaques? Edit: I see that you're addressing this somewhat in the next section, but I'm still curious about the plaques if you know!
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Collectively, these data suggest that haploinsufficiency of PPT1 alone favors an amyloidogenic program.
Really interesting.
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Lysosomal enzyme genes not identified in the human genetic analysis
These were not identified in your initial analysis of the 44 lysosomal enzyme genes and the CEU AD patients or in the proteomic analysis with the 3 late-stage patients, or both?
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44 lysosomal enzyme genes
How and why did you pick these 44? Also, I may have missed it but do you list anywhere what these 44 genes are?
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Collectively, these data strongly suggest that heterozygosity of multiple lysosomal enzyme genes represent risk factors for AD and may identify precise therapeutic targets for a subset of genetically-defined AD patients.
This is a really interesting and well-done paper connecting lysosomal proteins (often involved in lysosomal storage disorders) to AD. I think it opens up a lot of possibilities for future directions in relation to AD, LSDs, and the connection, and I'm excited to see what's next!
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