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Browsing by Author "Griffin, Edward F."

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    ApoE-associated modulation of neuroprotection from A beta-mediated neurodegeneration in transgenic Caenorhabditis elegans
    (Company of Biologists, 2019) Griffin, Edward F.; Scopel, Samuel E.; Stephen, Cayman A.; Holzhauer, Adam C.; Vaji, Madeline A.; Tuckey, Ryan A.; Berkowitz, Laura A.; Caldwell, Kim A.; Caldwell, Guy A.; University of Alabama Tuscaloosa; University of Alabama Birmingham
    Allele-specific distinctions in the human apolipoprotein E (APOE) locus represent the best-characterized genetic predictor of Alzheimer's disease (AD) risk. Expression of isoform APOE epsilon 2 is associated with reduced risk, while APOE epsilon 3 is neutral and APOE epsilon 4 carriers exhibit increased susceptibility. Using Caenorhabditis elegans, we generated a novel suite of humanized transgenic nematodes to facilitate neuronal modeling of amyloid-beta peptide (A beta) co-expression in the context of distinct human APOE alleles. We found that co-expression of human APOE epsilon 2 with A beta attenuated A beta-induced neurodegeneration, whereas expression of the APOE epsilon 4 allele had no effect on neurodegeneration, indicating a loss of neuroprotective capacity. Notably, the APOE epsilon 3 allele displayed an intermediate phenotype; it was not neuroprotective in young adults but attenuated neurodegeneration in older animals. There was no functional impact from the three APOE isoforms in the absence of A beta co-expression. Pharmacological treatment that examined neuroprotective effects of APOE alleles on calcium homeostasis showed allele-specific responses to changes in ER-associated calcium dynamics in the A beta background. Additionally, A beta suppressed survival, an effect that was rescued by APOE epsilon 2 and APOE epsilon 3, but not APOE epsilon 4. Expression of the APOE alleles in neurons, independent of A beta, exerted no impact on survival. Taken together, these results illustrate that C. elegans provides a powerful in vivo platform with which to explore how AD-associated neuronal pathways are modulated by distinct APOE gene products in the context of A beta-associated neurotoxicity. The significance of both ApoE and A beta to AD highlights the utility of this new pre-clinical model as a means to dissect their functional inter-relationship.
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    Distinct functional roles of Vps41-mediated neuroprotection in Alzheimer's and Parkinson's disease models of neurodegeneration
    (Oxford University Press, 2018) Griffin, Edward F.; Yan, Xiaohui; Caldwell, Kim A.; Caldwell, Guy A.; University of Alabama Tuscaloosa; University of Alabama Birmingham
    Commonalities and, in some cases, pathological overlap between neurodegenerative diseases have led to speculation that targeting of underlying mechanisms might be of potentially shared therapeutic benefit. Alzheimer's disease is characterized by the formation of plaques, composed primarily of the amyloid-beta 1-42 (A beta) peptide in the brain, resulting in neurodegeneration. Previously, we have shown that overexpression of the lysosomal-trafficking protein, human Vps41 (hVps41), is neuroprotective in a transgenic worm model of Parkinson's disease, wherein progressive dopaminergic neurodegeneration is induced by alpha-synuclein overexpression. Here, we report the results of a systematic comparison of hVps41-mediated neuroprotection between alpha-synuclein and A beta in transgenic nematode models of Caenorhabditis elegans. Our results indicate that an ARF-like GTPase gene product, ARL-8, mitigates endocytic neurodegeneration in a VPS-41-dependent manner, rather than through RAB-7 and AP3 as with alpha-synuclein. Furthermore, the neuroprotective effect of ARL-8 or hVps41 appears to be dependent on their colocalization and the activity of ARL-8. Additionally, we demonstrate that the LC3 orthologue, LGG-2, plays a critical role in A beta toxicity with ARL-8. Further analysis of functional effectors of A beta protein processing via the lysosomal pathway will assist in the elucidation of the underlying mechanism involving VPS-41-mediated neuroprotection. These results reveal functional distinctions in the intracellular management of neurotoxic proteins that serve to better inform the path for development of therapeutic interventions to halt neurodegeneration.
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    Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation
    (Wiley, 2021) van der Welle, Reini E. N.; Jobling, Rebekah; Burns, Christian; Sanza, Paolo; van der Beek, Jan A.; Fasano, Alfonso; Chen, Lan; Zwartkruis, Fried J.; Zwakenberg, Susan; Griffin, Edward F.; ten Brink, Corlinda; Veenendaal, Tineke; Liv, Nalan; van Ravenswaaij-Arts, Conny M. A.; Lemmink, Henny H.; Pfundt, Rolph; Blaser, Susan; Sepulveda, Carolina; Lozano, Andres M.; Yoon, Grace; Santiago-Sim, Teresa; Asensio, Cedric S.; Caldwell, Guy A.; Caldwell, Kim A.; Chitayat, David; Klumperman, Judith; Utrecht University; Utrecht University Medical Center; University of Toronto; Hospital for Sick Children (SickKids); University of Denver; University Health Network Toronto; Krembil Research Institute; University of Alabama Tuscaloosa; University of Alabama Birmingham; University of Groningen; Radboud University Nijmegen
    Vacuolar protein sorting 41 (VPS41) is as part of the Homotypic fusion and Protein Sorting (HOPS) complex required for lysosomal fusion events and, independent of HOPS, for regulated secretion. Here, we report three patients with compound heterozygous mutations in VPS41 (VPS41(S285P) and VPS41(R662)*; VPS41(c.1423-2A>G) and VPS41(R662)*) displaying neurodegeneration with ataxia and dystonia. Cellular consequences were investigated in patient fibroblasts and VPS41-depleted HeLa cells. All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo. By contrast, VPS41(S285P) enabled regulated secretion. Strikingly, loss of VPS41 function caused a cytosolic redistribution of mTORC1, continuous nuclear localization of Transcription Factor E3 (TFE3), enhanced levels of LC3II, and a reduced autophagic response to nutrient starvation. Phosphorylation of mTORC1 substrates S6K1 and 4EBP1 was not affected. In a C. elegans model of Parkinson's disease, co-expression of VPS41(S285P)/VPS41(R662)* abolished the neuroprotective function of VPS41 against alpha-synuclein aggregates. We conclude that the VPS41 variants specifically abrogate HOPS function, which interferes with the TFEB/TFE3 axis of mTORC1 signaling, and cause a neurodegenerative disease.
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    Vacuolar protein sorting protein 41 (VPS41) at an intersection of endosomal traffic in neurodegenerative disease
    (Wolters Kluwer, 2019) Griffin, Edward F.; Caldwell, Kim A.; Caldwell, Guy A.; University of Alabama Tuscaloosa; University of Alabama Birmingham