Dimitri Krainc

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Dimitri Krainc is a Slovenian-born American physician-scientist who is the Aaron Montgomery Ward Professor and Chairman of the Ken & Ruth Davee Department of Neurology and Director of the Feinberg Neuroscience Institute and the Simpson Querrey Center for Neurogenetics at Northwestern University Feinberg School of Medicine. [1]  After completing his medical training at the University of Zagreb, Krainc spent more than two decades at the Massachusetts General Hospital and Harvard Medical School, where he completed his research and clinical training and served on faculty until relocating to Northwestern University in 2013. [2] He has dedicated his scientific career to studying molecular pathways in the pathogenesis of neurodegeneration. Informed by genetic causes of disease, his work has uncovered key mechanisms across different neurodegenerative disorders that have led to pioneering design and development of targeted therapies. He has received numerous awards and recognitions for his work, including the Javits Neuroscience Investigator Award [3] and the Outstanding Investigator award from NIH, [4] and was elected to the Association of American Physicians, the National Academy of Medicine, the National Academy of Inventors [5] and the Croatian Academy of Sciences and Arts [6] He is the principal founding scientist of two biotech companies [7] and serves as Venture Partner at OrbiMed. [8] Krainc is President-elect of the American Neurological Association. [9]

Selected publications

Related Research Articles

<span class="mw-page-title-main">Lysosome</span> Cell membrane organelle

A lysosome is a single membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that digest many kinds of biomolecules. A lysosome has a specific composition, of both its membrane proteins and its lumenal proteins. The lumen's pH (~4.5–5.0) is optimal for the enzymes involved in hydrolysis, analogous to the activity of the stomach. Besides degradation of polymers, the lysosome is involved in cell processes of secretion, plasma membrane repair, apoptosis, cell signaling, and energy metabolism.

<span class="mw-page-title-main">Gaucher's disease</span> Medical condition

Gaucher's disease or Gaucher disease (GD) is a genetic disorder in which glucocerebroside accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelet count and enlargement of the liver and spleen, and is caused by a hereditary deficiency of the enzyme glucocerebrosidase, which acts on glucocerebroside. When the enzyme is defective, glucocerebroside accumulates, particularly in white blood cells and especially in macrophages. Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow.

<span class="mw-page-title-main">Lysosomal storage disease</span> Medical condition

Lysosomal storage diseases are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it.

<span class="mw-page-title-main">Parkin (protein)</span>

Parkin is a 465-amino acid residue E3 ubiquitin ligase, a protein that in humans and mice is encoded by the PARK2 gene. Parkin plays a critical role in ubiquitination – the process whereby molecules are covalently labelled with ubiquitin (Ub) and directed towards degradation in proteasomes or lysosomes. Ubiquitination involves the sequential action of three enzymes. First, an E1 ubiquitin-activating enzyme binds to inactive Ub in eukaryotic cells via a thioester bond and mobilises it in an ATP-dependent process. Ub is then transferred to an E2 ubiquitin-conjugating enzyme before being conjugated to the target protein via an E3 ubiquitin ligase. There exists a multitude of E3 ligases, which differ in structure and substrate specificity to allow selective targeting of proteins to intracellular degradation.

<span class="mw-page-title-main">Glucocerebrosidase</span> Mammalian protein found in humans

β-Glucocerebrosidase is an enzyme with glucosylceramidase activity that cleaves by hydrolysis the β-glycosidic linkage of the chemical glucocerebroside, an intermediate in glycolipid metabolism that is abundant in cell membranes. It is localized in the lysosome, where it remains associated with the lysosomal membrane. β-Glucocerebrosidase is 497 amino acids in length and has a molecular mass of 59,700 Da.

<span class="mw-page-title-main">Huntingtin</span> Gene and protein involved in Huntingtons disease

Huntingtin(Htt) is the protein coded for in humans by the HTT gene, also known as the IT15 ("interesting transcript 15") gene. Mutated HTT is the cause of Huntington's disease (HD), and has been investigated for this role and also for its involvement in long-term memory storage.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system disease

A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic.Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

<span class="mw-page-title-main">Ambroxol</span> Pharmaceutical drug

Ambroxol is a drug that breaks up phlegm, used in the treatment of respiratory diseases associated with viscid or excessive mucus. Ambroxol is often administered as an active ingredient in cough syrup.

<span class="mw-page-title-main">LRRK2</span> Protein kinase found in humans

Leucine-rich repeat kinase 2 (LRRK2), also known as dardarin and PARK8, is a large, multifunctional kinase enzyme that in humans is encoded by the LRRK2 gene. LRRK2 is a member of the leucine-rich repeat kinase family. Variants of this gene are associated with an increased risk of Parkinson's disease and Crohn's disease.

<span class="mw-page-title-main">DNM1L</span> Protein-coding gene in humans

Dynamin-1-like protein is a GTPase that regulates mitochondrial fission. In humans, dynamin-1-like protein, which is typically referred to as dynamin-related protein 1 (Drp1), is encoded by the DNM1L gene and is part of the dynamin superfamily (DSP) family of proteins.

<span class="mw-page-title-main">PQBP1</span> Protein-coding gene in the species Homo sapiens

Polyglutamine-binding protein 1 (PQBP1) is a protein that in humans is encoded by the PQBP1 gene.

<span class="mw-page-title-main">VPS35</span> Protein-coding gene in the species Homo sapiens

Vacuolar protein sorting ortholog 35 (VPS35) is a protein involved in autophagy and is implicated in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). VPS35 is part of a complex called the retromer, which is responsible for transporting select cargo proteins between vesicular structures and the Golgi apparatus. Mutations in the VPS35 gene (VPS35) cause aberrant autophagy, where cargo proteins fail to be transported and dysfunctional or unnecessary proteins fail to be degraded. There are numerous pathways affected by altered VPS35 levels and activity, which have clinical significance in neurodegeneration. There is therapeutic relevance for VPS35, as interventions aimed at correcting VPS35 function are in speculation.

Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described in 1915 by Margaret Reed Lewis and Warren Harmon Lewis. Ashford and Porter used electron microscopy to observe mitochondrial fragments in liver lysosomes by 1962, and a 1977 report suggested that "mitochondria develop functional alterations which would activate autophagy." The term "mitophagy" was in use by 1998.

<span class="mw-page-title-main">Pridopidine</span> Chemical compound

Pridopidine is an orally administrated small molecule investigational drug. Pridopidine is a selective and potent Sigma-1 Receptor agonist. It is being developed by Prilenia Therapeutics and is currently in late-stage clinical development for Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS).

<span class="mw-page-title-main">Autophagosome</span> Cell biology structure

An autophagosome is a spherical structure with double layer membranes. It is the key structure in macroautophagy, the intracellular degradation system for cytoplasmic contents. After formation, autophagosomes deliver cytoplasmic components to the lysosomes. The outer membrane of an autophagosome fuses with a lysosome to form an autolysosome. The lysosome's hydrolases degrade the autophagosome-delivered contents and its inner membrane.

<span class="mw-page-title-main">Jonathan Sackner-Bernstein</span> American physician (born 1961)

Jonathan Sackner-Bernstein is an American physician. He has published around 80 scientific articles, which have been cited more than 4,000 times. His research has ranged from cardiac care to the efficacy of drugs. His research led to increased scrutiny of Nesiritide, a widely marketed drug, which led to its decline in its use.

D. James "Jim" Surmeier, an American neuroscientist and physiologist of note, is the Nathan Smith Davis Professor and Chair in the Department of Neuroscience at Northwestern University Feinberg School of Medicine. His research is focused on the cellular physiology and circuit properties of the basal ganglia in health and disease, primarily Parkinson's and Huntington's disease as well as pain.

<span class="mw-page-title-main">Ana Maria Cuervo</span> Spanish scientist and biochemist

Ana Maria Cuervo is a Spanish-American physician, researcher, and cell biologist. She is a professor in developmental and molecular biology, anatomy and structural biology, and medicine and co-director of the Institute for Aging Studies at the Albert Einstein College of Medicine. She is best known for her research work on autophagy, the process by which cells recycle waste products, and its changes in aging and age-related diseases.

<span class="mw-page-title-main">Erika Holzbaur</span> American biologist

Erika L F. Holzbaur is an American biologist who is the William Maul Measey Professor of Physiology at University of Pennsylvania Perelman School of Medicine. Her research considers the dynamics of organelle motility along cytoskeleton of cells. She is particularly interested in the molecular mechanisms that underpin neurodegenerative diseases.

<span class="mw-page-title-main">Parkinson's disease in South Asians</span>

Epidemiological studies have shown lower age-related prevalence of Parkinson's disease in South Asians, with the rate of prevalence being around 52.7 per 100,000 as compared to a higher prevalence rate observed in populations with European origin, 108-257 per 100,000. Additionally, several studies have seen a higher prevalence of in women which contrasts with global data that observes a overall higher prevalence seen in men. Compared to most of the rest of the world, the South Asian countries seem to be on the lower end of PD prevalence. However, this is not to say that PD is not of concern in these countries. Over the past couple of years, the rate of Parkinson's has gone up in South Asia meaning that it is of high importance to study this pathological disease in these populations.

References

  1. "Faculty Profile". www.neurology.northwestern.edu. Retrieved 2022-10-11.
  2. Medicine, Northwestern. "Dimitri Krainc, MD, PhD". Northwestern Medicine. Retrieved 2022-10-11.
  3. "Dimitri Krainc | National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. Retrieved 2022-10-11.
  4. "Krainc to Receive $9 Million, 8-Year NIH Grant". Breakthroughs for Physicians. Retrieved 2022-10-11.
  5. Dimmer, Olivia (2023-12-12). "Krainc Elected to National Academy of Inventors". News Center. Retrieved 2023-12-13.
  6. "HAZU – Hrvatska akademija znanosti i umjetnosti". www.info.hazu.hr. Retrieved 2024-08-26.
  7. "Dimitri Krainc, MD, Ph.D." Vanqua Bio. Retrieved 2022-10-11.
  8. "Leadership | OrbiMed" . Retrieved 2023-01-09.
  9. Dimmer, Olivia (2023-08-22). "Krainc Elected President of American Neurological Association". News Center. Retrieved 2023-08-23.
  10. Wong, Yvette C.; Ysselstein, Daniel; Krainc, Dimitri (2018-02-15). "Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis". Nature. 554 (7692): 382–386. Bibcode:2018Natur.554..382W. doi:10.1038/nature25486. ISSN   1476-4687. PMC   6209448 . PMID   29364868.
  11. Burbulla, Lena F.; Song, Pingping; Mazzulli, Joseph R.; Zampese, Enrico; Wong, Yvette C.; Jeon, Sohee; Santos, David P.; Blanz, Judith; Obermaier, Carolin D.; Strojny, Chelsee; Savas, Jeffrey N.; Kiskinis, Evangelos; Zhuang, Xiaoxi; Krüger, Rejko; Surmeier, D. James (2017-09-22). "Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease". Science. 357 (6357): 1255–1261. Bibcode:2017Sci...357.1255B. doi:10.1126/science.aam9080. ISSN   1095-9203. PMC   6021018 . PMID   28882997.
  12. Song, Pingping; Peng, Wesley; Sauve, Veronique; Fakih, Rayan; Xie, Zhong; Ysselstein, Daniel; Krainc, Talia; Wong, Yvette C.; Mencacci, Niccolò E.; Savas, Jeffrey N.; Surmeier, D. James; Gehring, Kalle; Krainc, Dimitri (2023-12-06). "Parkinson's disease-linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons". Neuron. 111 (23): 3775–3788.e7. doi:10.1016/j.neuron.2023.08.018. ISSN   1097-4199. PMID   37716354.
  13. Burbulla, Lena F.; Zheng, Jianbin; Song, Pingping; Jiang, Weilan; Johnson, Michaela E.; Brundin, Patrik; Krainc, Dimitri (2021-10-08). "Direct targeting of wild-type glucocerebrosidase by antipsychotic quetiapine improves pathogenic phenotypes in Parkinson's disease models". JCI Insight. 6 (19): e148649. doi:10.1172/jci.insight.148649. ISSN   2379-3708. PMC   8525588 . PMID   34622801.
  14. Ysselstein, Daniel; Nguyen, Maria; Young, Tiffany J.; Severino, Alex; Schwake, Michael; Merchant, Kalpana; Krainc, Dimitri (2019-12-05). "LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson's disease patients". Nature Communications. 10 (1): 5570. Bibcode:2019NatCo..10.5570Y. doi:10.1038/s41467-019-13413-w. ISSN   2041-1723. PMC   6895201 . PMID   31804465.
  15. Jeong, Hyunkyung; Cohen, Dena E.; Cui, Libin; Supinski, Andrea; Savas, Jeffrey N.; Mazzulli, Joseph R.; Yates, John R.; Bordone, Laura; Guarente, Leonard; Krainc, Dimitri (2011-12-18). "Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway". Nature Medicine. 18 (1): 159–165. doi:10.1038/nm.2559. ISSN   1546-170X. PMC   3509213 . PMID   22179316.
  16. Mazzulli, Joseph R.; Xu, You-Hai; Sun, Ying; Knight, Adam L.; McLean, Pamela J.; Caldwell, Guy A.; Sidransky, Ellen; Grabowski, Gregory A.; Krainc, Dimitri (2011-07-08). "Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies". Cell. 146 (1): 37–52. doi:10.1016/j.cell.2011.06.001. ISSN   1097-4172. PMC   3132082 . PMID   21700325.
  17. Jeong, Hyunkyung; Then, Florian; Melia, Thomas J.; Mazzulli, Joseph R.; Cui, Libin; Savas, Jeffrey N.; Voisine, Cindy; Paganetti, Paolo; Tanese, Naoko; Hart, Anne C.; Yamamoto, Ai; Krainc, Dimitri (2009-04-03). "Acetylation targets mutant huntingtin to autophagosomes for degradation". Cell. 137 (1): 60–72. doi:10.1016/j.cell.2009.03.018. ISSN   1097-4172. PMC   2940108 . PMID   19345187.
  18. Cui, Libin; Jeong, Hyunkyung; Borovecki, Fran; Parkhurst, Christopher N.; Tanese, Naoko; Krainc, Dimitri (2006-10-06). "Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration". Cell. 127 (1): 59–69. doi: 10.1016/j.cell.2006.09.015 . ISSN   0092-8674. PMID   17018277. S2CID   15656723.
  19. Zhai, Weiguo; Jeong, Hyunkyung; Cui, Libin; Krainc, Dimitri; Tjian, Robert (2005-12-29). "In vitro analysis of huntingtin-mediated transcriptional repression reveals multiple transcription factor targets". Cell. 123 (7): 1241–1253. doi: 10.1016/j.cell.2005.10.030 . ISSN   0092-8674. PMID   16377565. S2CID   15700502.
  20. Dunah, Anthone W.; Jeong, Hyunkyung; Griffin, April; Kim, Yong-Man; Standaert, David G.; Hersch, Steven M.; Mouradian, M. Maral; Young, Anne B.; Tanese, Naoko; Krainc, Dimitri (2002-06-21). "Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease". Science. 296 (5576): 2238–2243. Bibcode:2002Sci...296.2238D. doi:10.1126/science.1072613. ISSN   1095-9203. PMID   11988536. S2CID   21849663.