Konrad E Zinsmaier
- Department Head, Neuroscience
- Professor, Neuroscience
- Professor, Molecular and Cellular Biology
- Professor, Entomology / Insect Science - GIDP
- Professor, Physiological Sciences - GIDP
- Member of the Graduate Faculty
- Professor, Neuroscience - GIDP
Biography
My laboratory has a long-standing interest in understanding molecular mechanisms that facilitate synaptic function and plasticity, and mechanisms that protect synapses from neurodegeneration. In addition, we are interested in the specialized mechanisms of mitochondrial biology in axons and dendrites of neurons. We investigate these fundamental mechanisms by undertaking a multidisciplinary approach, exploiting the neuromuscular junction (NMJ) of genetically modified Drosophila as a model system. Currently, our research focuses on a) neuroprotective mechanism of synapses, b) molecular mechanisms that control regulated neurotransmitter release, and c) molecular mechanisms of mitochondrial transport and biology in axons. These projects use forward and reverse genetics to genetically dissect the role of key components that are conserved from invertebrates to mammals. Abnormal function is assayed by a variety of techniques including electrical recordings, electron microscopy, confocal microscopy, live imaging of intracellular calcium, endo- and exocytosis, and mitochondrial transport in axons of motor neurons.
Degrees
- Dr. rer. nat. Neuroscience and Genetics
- Julius Maximilian Universität, Würzburg, Bavaria, Germany
- Klonierung und Charakterisierung des immunhistochemisch identifizierten csp Gens von Drosophila melanogaster
Work Experience
- University of Arizona, Tucson, Arizona (2009 - Ongoing)
- University of Arizona, Tucson, Arizona (2008 - Ongoing)
- University of Arizona, Tucson, Arizona (2008 - Ongoing)
- University of Arizona, Tucson, Arizona (2008 - 2009)
- University of Arizona, Tucson, Arizona (2002 - 2008)
- University of Arizona, Tucson, Arizona (2002 - 2008)
- University of Pennsylvania School of Medicine (1995 - 2002)
- California Institute of Technology, Pasadena, California (1993 - 1995)
- California Institute of Technology, Pasadena, California (1990 - 1993)
Interests
Research
- neuroprotective mechanisms- molecular mechanisms of synaptic function and plasticity- molecular mechanisms of mitochondrial transport and survival in axons and dendrites of neurons
Teaching
aspects of molecular and cellular neuroscienceaspects of neurogeneticsmolecular mechanisms underlying neurological and neurodegenerative diseases
Courses
No activities entered.
Scholarly Contributions
Chapters
Journals/Publications
- More infoMutations in DNAJC5/CSPα are associated with adult neuronal ceroid lipofuscinosis (ANCL), a dominant-inherited neurodegenerative disease featuring lysosome-derived autofluorescent storage materials (AFSMs) termed lipofuscin. Functionally, DNAJC5 has been implicated in chaperoning synaptic proteins and in misfolding-associated protein secretion (MAPS), but how DNAJC5 dysfunction causes lipofuscinosis and neurodegeneration is unclear. Here we report two functionally distinct but coupled chaperoning activities of DNAJC5, which jointly regulate lysosomal homeostasis: While endolysosome-associated DNAJC5 promotes ESCRT-dependent microautophagy, a fraction of perinuclear and non-lysosomal DNAJC5 mediates MAPS. Functional proteomics identifies a previously unknown DNAJC5 interactor SLC3A2/CD98hc that is essential for the perinuclear DNAJC5 localization and MAPS but dispensable for microautophagy. Importantly, uncoupling these two processes, as seen in cells lacking SLC3A2 or expressing ANCL-associated DNAJC5 mutants, generates DNAJC5-containing AFSMs resembling NCL patient-derived lipofuscin and induces neurodegeneration in a Drosophila ANCL model. These findings suggest that MAPS safeguards microautophagy to avoid DNAJC5-associated lipofuscinosis and neurodegeneration.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; AFSM: autofluorescent storage materials; ANCL: adult neuronal ceroid lipofuscinosis; Baf. A1: bafilomycin A1; CLN: ceroid lipofuscinosis neuronal; CLU: clusterin; CS: cysteine string domain of DNAJC5/CSPα; CUPS: compartment for unconventional protein secretion; DN: dominant negative; DNAJC5/CSPα: DnaJ heat shock protein family (Hsp40) member C5; eMI: endosomal microautophagy; ESCRT: endosomal sorting complex required for transport; GFP: green fluorescent protein; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; INCL: infant neuronal ceroid lipofuscinosis; JNCL: juvenile neuronal ceroid lipofuscinosis; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAPTM4B: lysosomal protein transmembrane 4 beta; LN: linker domain of DNAJC5/CSPα; MAPS: misfolding-associated protein secretion; mCh/Ch: mCherry; mCi/Ci: mCitrine; MTOR: mechanistic target of rapamycin kinase; NCL: neuronal ceroid lipofuscinosis; PPT1: palmitoyl-protein thioesterase 1; PQC: protein quality control; SBP: streptavidin binding protein; SGT: small glutamine-rich tetratricopeptide repeat; shRNA: short hairpin RNA; SLC3A2/CD98hc: solute carrier family 3 member 2; SNCA/α-synuclein: synuclein alpha; TMED10: transmembrane p24 trafficking protein 10; UV: ultraviolet; VPS4: vacuolar protein sorting 4 homolog; WT: wild type.
