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Article ; Online: The Autophagy Lysosomal Pathway and Neurodegeneration.

Finkbeiner, Steven

Cold Spring Harbor perspectives in biology

2020 Volume 12, Issue 3

Abstract: The autophagy lysosomal pathway (ALP) is a major mechanism for degrading intracellular macromolecules. The catabolic products can then be used by the cell for energy or as building blocks to make other macromolecules. Since its discovery, a variety of ... ...

Abstract	The autophagy lysosomal pathway (ALP) is a major mechanism for degrading intracellular macromolecules. The catabolic products can then be used by the cell for energy or as building blocks to make other macromolecules. Since its discovery, a variety of cellular pathways have emerged that target components with varying specificity for lysosomal degradation. Under some circumstances, lysosomes may release their contents into the extracellular space where they may serve signaling or pathogenic functions. The ALP is active in healthy cells, and the level of activity can be regulated by nutrient-sensing and metabolic signaling pathways. The ALP is the primary pathway by which lipids and damaged organelles are degraded and may be the only pathway capable of degrading aggregated proteins. As such, there has been intense interest in understanding the role of the ALP in the accumulation of aggregated misfolded proteins characteristic of many of the major adult-onset neurodegenerative diseases. This review focuses on recent advances in our understanding of the ALP and its potential relationship to the pathogenesis and treatment of neurodegenerative diseases.
MeSH term(s)	Animals ; Autophagy/physiology ; Humans ; Lipids/chemistry ; Lysosomes/metabolism ; Molecular Chaperones/metabolism ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; Pinocytosis ; Signal Transduction/physiology
Chemical Substances	Lipids ; Molecular Chaperones
Language	English
Publishing date	2020-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	1943-0264
ISSN (online)	1943-0264
DOI	10.1101/cshperspect.a033993
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Article ; Online: Functional genomics, genetic risk profiling and cell phenotypes in neurodegenerative disease.

Finkbeiner, Steven

Neurobiology of disease

2020 Volume 146, Page(s) 105088

Abstract: Human genetics provides unbiased insights into the causes of human disease, which can be used to create a foundation for effective ways to more accurately diagnose patients, stratify patients for more successful clinical trials, discover and develop new ... ...

Abstract	Human genetics provides unbiased insights into the causes of human disease, which can be used to create a foundation for effective ways to more accurately diagnose patients, stratify patients for more successful clinical trials, discover and develop new therapies, and ultimately help patients choose the safest and most promising therapeutic option based on their risk profile. But the process for translating basic observations from human genetics studies into pathogenic disease mechanisms and treatments is laborious and complex, and this challenge has particularly slowed the development of interventions for neurodegenerative disease. In this review, we discuss the many steps in the process, the important considerations at each stage, and some of the latest tools and technologies that are available to help investigators translate insights from human genetics into diagnostic and therapeutic strategies that will lead to the sort of advances in clinical care that make a difference for patients.
MeSH term(s)	Cell Differentiation/genetics ; Genetic Diseases, Inborn/diagnosis ; Genetic Diseases, Inborn/genetics ; Genomics ; Humans ; Neurodegenerative Diseases/diagnosis ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/pathology ; Phenotype ; Risk
Language	English
Publishing date	2020-09-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2020.105088
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Article ; Online: Huntington's disease iPSC models-using human patient cells to understand the pathology caused by expanded CAG repeats.

Kaye, Julia / Reisine, Terry / Finkbeiner, Steven

Faculty reviews

2022 Volume 11, Page(s) 16

Abstract: A major advance in the study of Huntington's disease (HD) has been the development of human disease models employing induced pluripotent stem cells (iPSCs) derived from patients with HD. Because iPSCs provide an unlimited source of cells and can be ... ...

Abstract	A major advance in the study of Huntington's disease (HD) has been the development of human disease models employing induced pluripotent stem cells (iPSCs) derived from patients with HD. Because iPSCs provide an unlimited source of cells and can be obtained from large numbers of HD patients, they are a uniquely valuable tool for investigating disease mechanisms and for discovering potential disease-modifying therapeutics. Here, we summarize some of the important findings in HD pathophysiology that have emerged from studies of patient-derived iPSC lines. Because they retain the genome and actual disease mutations of the patient, they provide a cell source to investigate genetic contributions to the disease. iPSCs provide advantages over other disease models. While iPSC-based technology erases some epigenetic marks, newly developed transdifferentiation methods now let us investigate epigenetic factors that control expression of mutant huntingtin (mHTT). Human HD iPSC lines allow us to investigate how endogenous levels of mHTT affect cell health, in contrast to other models that often rely on overexpressing the protein. iPSCs can be differentiated into neurons and other disease-related cells such as astrocytes from different brain regions to study brain regional differences in the disease process, as well as the cell-cell dependencies involved in HD-associated neurodegeneration. They also serve as a tissue source to investigate factors that impact CAG repeat instability, which is involved in regional differences in neurodegeneration in the HD brain. Human iPSC models can serve as a powerful model system to identify genetic modifiers that may impact disease onset, progression, and symptomatology, providing novel molecular targets for drug discovery.
Language	English
Publishing date	2022-06-28
Publishing country	England
Document type	Journal Article ; Review
ISSN	2732-432X
ISSN (online)	2732-432X
DOI	10.12703/r/11-16
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Article ; Online: AutoComet: A fully automated algorithm to quickly and accurately analyze comet assays.

Barbé, Lise / Lam, Stephanie / Holub, Austin / Faghihmonzavi, Zohreh / Deng, Minnie / Iyer, Rajshri / Finkbeiner, Steven

Redox biology

2023 Volume 62, Page(s) 102680

Abstract: DNA damage is a common cellular feature seen in cancer and neurodegenerative disease, but fast and accurate methods for quantifying DNA damage are lacking. Comet assays are a biochemical tool to measure DNA damage based on the migration of broken DNA ... ...

Abstract	DNA damage is a common cellular feature seen in cancer and neurodegenerative disease, but fast and accurate methods for quantifying DNA damage are lacking. Comet assays are a biochemical tool to measure DNA damage based on the migration of broken DNA strands towards a positive electrode, which creates a quantifiable 'tail' behind the cell. However, a major limitation of this approach is the time needed for analysis of comets in the images with available open-source algorithms. The requirement for manual curation and the laborious pre- and post-processing steps can take hours to days. To overcome these limitations, we developed AutoComet, a new open-source algorithm for comet analysis that utilizes automated comet segmentation and quantification of tail parameters. AutoComet first segments and filters comets based on size and intensity and then filters out comets without a well-connected head and tail, which significantly increases segmentation accuracy. Because AutoComet is fully automated, it minimizes curator bias and is scalable, decreasing analysis time over ten-fold, to less than 3 s per comet. AutoComet successfully detected statistically significant differences in tail parameters between cells with and without induced DNA damage, and was more comparable to the results of manual curation than other open-source software analysis programs. We conclude that the AutoComet algorithm provides a fast, unbiased and accurate method to quantify DNA damage that avoids the inherent limitations of manual curation and will significantly improve the ability to detect DNA damage.
MeSH term(s)	Humans ; Comet Assay/methods ; Neurodegenerative Diseases ; Image Processing, Computer-Assisted/methods ; DNA Damage ; Algorithms
Language	English
Publishing date	2023-03-24
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2023.102680
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Article ; Online: Generation of two human induced pluripotent stem cell lines from fibroblasts of unrelated Parkinson's patients carrying the G2019S mutation in the LRRK2 gene (LCSBi005, LCSBi006).

Novak, Gabriela / Finkbeiner, Steven / Skibinski, Gaia / Skupin, Alexander

Stem cell research

2021 Volume 57, Page(s) 102569

Abstract: Mutations in the LRRK2 gene are known to mediate predisposition to Parkinson disease. Fibroblasts heterozygous for the G2019S LRRK2 mutation were obtained from a 53-year-old male patient with disease onset at 34 years (LCSBi005, ND29542), and from a 63- ... ...

Abstract	Mutations in the LRRK2 gene are known to mediate predisposition to Parkinson disease. Fibroblasts heterozygous for the G2019S LRRK2 mutation were obtained from a 53-year-old male patient with disease onset at 34 years (LCSBi005, ND29542), and from a 63-year-old male patient with disease onset at 56 years (LCSBi006, ND34267). Induced pluripotent stem cell (iPSC) clones were generated for each cell line using Sendai virus. The absence of chromosomal defects was confirmed using array comparative genomic hybridization. The cell lines express pluripotency markers and have the ability to differentiate into all three germ layers.
Language	English
Publishing date	2021-10-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2393143-7
ISSN	1876-7753 ; 1873-5061
ISSN (online)	1876-7753
ISSN	1873-5061
DOI	10.1016/j.scr.2021.102569
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Article ; Online: Generation of two human induced pluripotent stem cell lines (iPSCs) with mutations of the α-synuclein (SNCA) gene associated with Parkinson's disease; the A53T mutation (LCSBi003) and a triplication of the SNCA gene (LCSBi007).

Novak, Gabriela / Finkbeiner, Steven / Skibinski, Gaia / Skupin, Alexander

Stem cell research

2021 Volume 57, Page(s) 102600

Abstract: Mutations in the SNCA (α-synuclein, PARK1) gene significantly contribute to Parkinson's disease and SNCA inclusions are strongly associated with PD. Fibroblasts from a 51-year-old female patient with disease onset at 39 years, carrying the A53T SNCA ... ...

Abstract	Mutations in the SNCA (α-synuclein, PARK1) gene significantly contribute to Parkinson's disease and SNCA inclusions are strongly associated with PD. Fibroblasts from a 51-year-old female patient with disease onset at 39 years, carrying the A53T SNCA mutation (LCSBi003, ND40996), and fibroblasts with a triplication of the SNCA gene obtained from a 55-year-old female patient with disease onset at 52 years (LCSBi007, ND27760), were reprogrammed into human induced pluripotent stem cells (iPSCs) using Sendai virus. The presence of other genetic variants was determined using array comparative genomic hybridization. Presence of SNCA triplication was confirmed by FISH analysis.
Language	English
Publishing date	2021-11-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2393143-7
ISSN	1876-7753 ; 1873-5061
ISSN (online)	1876-7753
ISSN	1873-5061
DOI	10.1016/j.scr.2021.102600
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Article ; Online: The Arc of cognition: Signaling cascades regulating Arc and implications for cognitive function and disease.

Epstein, Irina / Finkbeiner, Steven

Seminars in cell & developmental biology

2018 Volume 77, Page(s) 63–72

Abstract: The activity-regulated cytoskeletal (Arc) gene is implicated in numerous synaptic plasticity paradigms, including long-term potentiation and depression and homeostatic plasticity, and is critical for consolidating memory. How Arc facilitates these forms ... ...

Abstract	The activity-regulated cytoskeletal (Arc) gene is implicated in numerous synaptic plasticity paradigms, including long-term potentiation and depression and homeostatic plasticity, and is critical for consolidating memory. How Arc facilitates these forms of plasticity is not fully understood. Unlike other neuronal immediate-early genes, Arc encodes a protein that shuttles between the somatodendritic and nuclear compartments to regulate synaptic plasticity. Little attention has been paid to Arc's role in the nucleus. Here, we highlight the regulatory elements and signaling cascades required to induce Arc transcription and discuss the significance of Arc nuclear localization for synaptic plasticity and scaling. We integrate these findings into the context of cognitive function and disease and propose a model in which Arc mediates an effect on memory as a "chaser" of synaptic activity through homeostatic scaling.
MeSH term(s)	Active Transport, Cell Nucleus/physiology ; Cell Nucleus/metabolism ; Cognition/physiology ; Cognition Disorders/pathology ; Cytoskeletal Proteins/metabolism ; Humans ; Memory/physiology ; Nerve Tissue Proteins/metabolism ; Neuronal Plasticity/physiology ; Neurons/metabolism ; Protein Biosynthesis/genetics ; Signal Transduction/physiology ; Synapses/metabolism
Chemical Substances	Cytoskeletal Proteins ; Nerve Tissue Proteins ; activity regulated cytoskeletal-associated protein
Language	English
Publishing date	2018-03-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1312473-0
ISSN	1096-3634 ; 1084-9521
ISSN (online)	1096-3634
ISSN	1084-9521
DOI	10.1016/j.semcdb.2017.09.023
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Article ; Online: Huntington's Disease.

Finkbeiner, Steven

Cold Spring Harbor perspectives in biology

2011 Volume 3, Issue 6

Abstract: Huntington's disease (HD) is the most common inherited neurodegenerative disease and is characterized by uncontrolled excessive motor movements and cognitive and emotional deficits. The mutation responsible for HD leads to an abnormally long ... ...

Abstract	Huntington's disease (HD) is the most common inherited neurodegenerative disease and is characterized by uncontrolled excessive motor movements and cognitive and emotional deficits. The mutation responsible for HD leads to an abnormally long polyglutamine (polyQ) expansion in the huntingtin (Htt) protein, which confers one or more toxic functions to mutant Htt leading to neurodegeneration. The polyQ expansion makes Htt prone to aggregate and accumulate, and manipulations that mitigate protein misfolding or facilitate the clearance of misfolded proteins tend to slow disease progression in HD models. This article will focus on HD and the evidence that it is a conformational disease.
MeSH term(s)	Aging ; DNA Repeat Expansion ; Genetic Association Studies ; Humans ; Huntingtin Protein ; Huntington Disease/genetics ; Huntington Disease/metabolism ; Huntington Disease/pathology ; Inclusion Bodies/metabolism ; Inclusion Bodies/pathology ; Molecular Chaperones/physiology ; Nerve Tissue Proteins/chemistry ; Nerve Tissue Proteins/genetics ; Nuclear Proteins/chemistry ; Nuclear Proteins/genetics ; Peptides/chemistry ; Protein Folding
Chemical Substances	HTT protein, human ; Huntingtin Protein ; Molecular Chaperones ; Nerve Tissue Proteins ; Nuclear Proteins ; Peptides ; polyglutamine (26700-71-0)
Language	English
Publishing date	2011-06-01
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1943-0264
ISSN (online)	1943-0264
DOI	10.1101/cshperspect.a007476
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Article ; Online: Fluorescently labeled nuclear morphology is highly informative of neurotoxicity.

Wang, Shijie / Linsley, Jeremy W / Linsley, Drew A / Lamstein, Josh / Finkbeiner, Steven

Frontiers in toxicology

2022 Volume 4, Page(s) 935438

Abstract: Neurotoxicity can be detected in live microscopy by morphological changes such as retraction of neurites, fragmentation, blebbing of the neuronal soma and ultimately the disappearance of fluorescently labeled neurons. However, quantification of these ... ...

Abstract	Neurotoxicity can be detected in live microscopy by morphological changes such as retraction of neurites, fragmentation, blebbing of the neuronal soma and ultimately the disappearance of fluorescently labeled neurons. However, quantification of these features is often difficult, low-throughput, and imprecise due to the overreliance on human curation. Recently, we showed that convolutional neural network (CNN) models can outperform human curators in the assessment of neuronal death from images of fluorescently labeled neurons, suggesting that there is information within the images that indicates toxicity but that is not apparent to the human eye. In particular, the CNN's decision strategy indicated that information within the nuclear region was essential for its superhuman performance. Here, we systematically tested this prediction by comparing images of fluorescent neuronal morphology from nuclear-localized fluorescent protein to those from freely diffused fluorescent protein for classifying neuronal death. We found that biomarker-optimized (BO-) CNNs could learn to classify neuronal death from fluorescent protein-localized nuclear morphology (mApple-NLS-CNN) alone, with super-human accuracy. Furthermore, leveraging methods from explainable artificial intelligence, we identified novel features within the nuclear-localized fluorescent protein signal that were indicative of neuronal death. Our findings suggest that the use of a nuclear morphology marker in live imaging combined with computational models such mApple-NLS-CNN can provide an optimal readout of neuronal death, a common result of neurotoxicity.
Language	English
Publishing date	2022-08-24
Publishing country	Switzerland
Document type	Journal Article
ISSN	2673-3080
ISSN (online)	2673-3080
DOI	10.3389/ftox.2022.935438
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Article ; Online: Generation of two human induced pluripotent stem cell lines from fibroblasts of Parkinson's disease patients carrying the ILE368ASN mutation in PINK1 (LCSBi002) and the R275W mutation in Parkin (LCSBI004).

Novak, Gabriela / Finkbeiner, Steven / Skibinski, Gaia / Bernini, Michela / Donato, Cristina / Skupin, Alexander

Stem cell research

2022 Volume 61, Page(s) 102765

Abstract: Mutations in PINK1 and Parkin are two of the main causes of recessive early-onset Parkinson's disease (PD). We generated human induced pluripotent stem cells (hiPSCs) from fibroblasts of a 64-year-old male patient with a homozygous ILE368ASN mutation in ... ...

Abstract	Mutations in PINK1 and Parkin are two of the main causes of recessive early-onset Parkinson's disease (PD). We generated human induced pluripotent stem cells (hiPSCs) from fibroblasts of a 64-year-old male patient with a homozygous ILE368ASN mutation in PINK1, who experienced disease onset at 33 years, and from fibroblasts of a 61-year-old female patient heterozygous for the R275W mutation in Parkin, who experienced disease onset at 44 years. Array comparative genomic hybridization (aCGH) determined genotypic variation in each line. The cell lines were successfully used to generate midbrain dopaminergic neurons, the neuron type primarily affected in PD.
MeSH term(s)	Comparative Genomic Hybridization ; Dopaminergic Neurons/metabolism ; Female ; Fibroblasts/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Male ; Middle Aged ; Mutation/genetics ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; Protein Kinases/genetics ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2022-03-29
Publishing country	England
Document type	Case Reports ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2393143-7
ISSN	1876-7753 ; 1873-5061
ISSN (online)	1876-7753
ISSN	1873-5061
DOI	10.1016/j.scr.2022.102765
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