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Article ; Online: Cholecystokinin Activation of Cholecystokinin 1 Receptors: a Purkinje Cell Neuroprotective Pathway.

Orr, Harry T

2022 Volume 22, Issue 4, Page(s) 756–760

Abstract: This is a summary of the virtual presentation given at the 2021 meeting of the Society for Research on the Cerebellum and Ataxias, https://www.meetings.be/SRCA2021/ , where the therapeutic potential of the CCK-CCK1R pathway for treating diseases ... ...

Abstract	This is a summary of the virtual presentation given at the 2021 meeting of the Society for Research on the Cerebellum and Ataxias, https://www.meetings.be/SRCA2021/ , where the therapeutic potential of the CCK-CCK1R pathway for treating diseases involving Purkinje cell degeneration was presented. Spinocerebellar ataxia type 1 (SCA1) is one of a group of almost 50 genetic diseases characterized by the degeneration of cerebellar Purkinje cells. The SCA1 Pcp2-ATXN1[30Q]D776 mouse model displays ataxia, i.e. Purkinje cell dysfunction, but lacks progressive Purkinje cell degeneration. RNA-seq revealed increased expression of cholecystokinin (CCK) in cerebella of Pcp2-ATXN1[30Q]D776 mice. Importantly, the absence of Cck1 receptor (CCK1R) in Pcp2-ATXN1[30Q]D776 mice conferred a progressive degenerative disease with Purkinje cell loss. Administration of a CCK1R agonist to Pcp2-AXTN1[82Q] mice reduced Purkinje cell pathology and associated deficits in motor performance. In addition, administration of the CCK1R agonist improved motor performance of Pcp2-ATXN2[127Q] SCA2 mice. Furthermore, CCK1R activation corrected mTORC1 signaling and improved the expression of calbindin in the cerebella of AXTN1[82Q] and ATXN2[127Q] mice. These results support the Cck-Cck1R pathway is a potential therapeutic target for the treatment of diseases involving Purkinje neuron degeneration.
MeSH term(s)	Mice ; Animals ; Purkinje Cells/physiology ; Cholecystokinin/pharmacology ; Cholecystokinin/metabolism ; Receptors, Cholecystokinin/metabolism ; Ataxin-1/genetics ; Mice, Transgenic ; Spinocerebellar Ataxias/genetics ; Cerebellum/pathology ; Ataxia/genetics ; Disease Models, Animal
Chemical Substances	Cholecystokinin (9011-97-6) ; Receptors, Cholecystokinin ; Ataxin-1
Language	English
Publishing date	2022-06-23
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2112586-7
ISSN	1473-4230 ; 1473-4222
ISSN (online)	1473-4230
ISSN	1473-4222
DOI	10.1007/s12311-022-01428-x
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Zs.A 5795: Show issues

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Article ; Online: HD and SCA1: Tales from two 30-year journeys since gene discovery.

Thompson, Leslie M / Orr, Harry T

Neuron

2023 Volume 111, Issue 22, Page(s) 3517–3530

Abstract: One of the more transformative findings in human genetics was the discovery that the expansion of unstable nucleotide repeats underlies a group of inherited neurological diseases. A subset of these unstable repeat neurodegenerative diseases is due to the ...

Abstract	One of the more transformative findings in human genetics was the discovery that the expansion of unstable nucleotide repeats underlies a group of inherited neurological diseases. A subset of these unstable repeat neurodegenerative diseases is due to the expansion of a CAG trinucleotide repeat encoding a stretch of glutamines, i.e., the polyglutamine (polyQ) repeat neurodegenerative diseases. Among the CAG/polyQ repeat diseases are Huntington's disease (HD) and spinocerebellar ataxia type 1 (SCA1), in which the expansions are within widely expressed proteins. Although both HD and SCA1 are autosomal dominantly inherited, and both typically cause mid- to late-life-onset movement disorders with cognitive decline, they each are characterized by distinct clinical characteristics and predominant sites of neuropathology. Importantly, the respective affected proteins, Huntingtin (HTT, HD) and Ataxin 1 (ATXN1, SCA1), have unique functions and biological properties. Here, we review HD and SCA1 with a focus on how their disease-specific and shared features may provide informative insights.
MeSH term(s)	Humans ; Huntington Disease/genetics ; Spinocerebellar Ataxias/genetics ; Ataxin-1/genetics ; Proteins/genetics ; Trinucleotide Repeats ; Nervous System Diseases/genetics ; Genetic Association Studies ; Trinucleotide Repeat Expansion/genetics
Chemical Substances	Ataxin-1 ; Proteins
Language	English
Publishing date	2023-10-19
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2023.09.036
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Zs.A 2496: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The PERK pathway: beneficial or detrimental for neurodegenerative diseases and tumor growth and cancer.

Talukdar, Gourango / Orr, Harry T / Lei, Zhixin

Human molecular genetics

2023 Volume 32, Issue 16, Page(s) 2545–2557

Abstract: Protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) is one of the three major sensors in the unfolded protein response (UPR). The UPR is involved in the modulation of protein synthesis as an adaptive response. Prolonged PERK activity ... ...

Abstract	Protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) is one of the three major sensors in the unfolded protein response (UPR). The UPR is involved in the modulation of protein synthesis as an adaptive response. Prolonged PERK activity correlates with the development of diseases and the attenuation of disease severity. Thus, the current debate focuses on the role of the PERK signaling pathway either in accelerating or preventing diseases such as neurodegenerative diseases, myelin disorders, and tumor growth and cancer. In this review, we examine the current findings on the PERK signaling pathway and whether it is beneficial or detrimental for the above-mentioned disorders.
MeSH term(s)	Humans ; Endoplasmic Reticulum Stress/genetics ; Neurodegenerative Diseases/metabolism ; eIF-2 Kinase/genetics ; eIF-2 Kinase/metabolism ; Unfolded Protein Response ; Neoplasms/genetics
Chemical Substances	eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2023-06-29
Publishing country	England
Document type	Review ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddad103
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Zs.A 3469: Show issues

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Article ; Online: Toxic RNA as a driver of disease in a common form of ALS and dementia.

Orr, Harry T

Proceedings of the National Academy of Sciences of the United States of America

2013 Volume 110, Issue 19, Page(s) 7533–7534

MeSH term(s)	Amyotrophic Lateral Sclerosis/genetics ; Animals ; DNA Repeat Expansion ; Frontotemporal Dementia/genetics ; Humans
Language	English
Publishing date	2013-04-29
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1305239110
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Zs.A 1148: Show issues

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Article: Increased intrinsic membrane excitability is associated with hypertrophic olivary degeneration in spinocerebellar ataxia type 1.

Morrison, Logan M / Huang, Haoran / Handler, Hillary P / Fu, Min / Bushart, David D / Pappas, Samuel S / Orr, Harry T / Shakkottai, Vikram G

bioRxiv : the preprint server for biology

2023

Abstract: One of the characteristic areas of brainstem degeneration across multiple spinocerebellar ataxias (SCAs) is the inferior olive (IO), a medullary nucleus that plays a key role in motor learning. In addition to its vulnerability in SCAs, the IO is also ... ...

Abstract	One of the characteristic areas of brainstem degeneration across multiple spinocerebellar ataxias (SCAs) is the inferior olive (IO), a medullary nucleus that plays a key role in motor learning. In addition to its vulnerability in SCAs, the IO is also susceptible to a distinct pathology known as hypertrophic olivary degeneration (HOD). Clinically, HOD has been exclusively observed after lesions in the brainstem disrupt inhibitory afferents to the IO. Here, for the first time, we describe HOD in another context: spinocerebellar ataxia type 1 (SCA1). Using the genetically-precise SCA1 knock-in mouse model (SCA1-KI; both sexes used), we assessed SCA1-associated changes in IO neuron structure and function. Concurrent with degeneration, we found that SCA1-KI IO neurons are hypertrophic, exhibiting early dendrite lengthening and later somatic expansion. Unlike in previous descriptions of HOD, we observed no clear loss of IO inhibitory innervation; nevertheless, patch-clamp recordings from brainstem slices reveal that SCA1-KI IO neurons are hyperexcitable. Rather than synaptic disinhibition, we identify increases in
Language	English
Publishing date	2023-10-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.23.563657
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Article ; Online: Cell biology of spinocerebellar ataxia.

Orr, Harry T

The Journal of cell biology

2012 Volume 197, Issue 2, Page(s) 167–177

Abstract: Ataxia is a neurological disorder characterized by loss of control of body movements. Spinocerebellar ataxia (SCA), previously known as autosomal dominant cerebellar ataxia, is a biologically robust group of close to 30 progressive neurodegenerative ... ...

Abstract	Ataxia is a neurological disorder characterized by loss of control of body movements. Spinocerebellar ataxia (SCA), previously known as autosomal dominant cerebellar ataxia, is a biologically robust group of close to 30 progressive neurodegenerative diseases. Six SCAs, including the more prevalent SCA1, SCA2, SCA3, and SCA6 along with SCA7 and SCA17 are caused by expansion of a CAG repeat that encodes a polyglutamine tract in the affected protein. How the mutated proteins in these polyglutamine SCAs cause disease is highly debated. Recent work suggests that the mutated protein contributes to pathogenesis within the context of its "normal" cellular function. Thus, understanding the cellular function of these proteins could aid in the development of therapeutics.
MeSH term(s)	Amino Acid Sequence ; Ataxin-1 ; Ataxins ; Humans ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Peptides/chemistry ; Protein Biosynthesis ; RNA Splicing Factors ; RNA-Binding Proteins/metabolism ; Signal Transduction ; Spinocerebellar Ataxias/genetics ; Trinucleotide Repeat Expansion ; Trinucleotide Repeats
Chemical Substances	ATXN1 protein, human ; Ataxin-1 ; Ataxins ; Nerve Tissue Proteins ; Nuclear Proteins ; Peptides ; RBM17 protein, human ; RNA Splicing Factors ; RNA-Binding Proteins ; polyglutamine (26700-71-0)
Language	English
Publishing date	2012-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.201105092
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Article ; Online: Polyglutamine neurodegeneration: expanded glutamines enhance native functions.

Orr, Harry T

Current opinion in genetics & development

2012 Volume 22, Issue 3, Page(s) 251–255

Abstract: An intriguing set of neurodegenerative disease are the nine disorders caused by the expansion of a unstable trinucleotide CAG repeat where the repeat is located within the coding of the affected gene, that is, the polyglutamine (polyQ) diseases. A gain- ... ...

Abstract	An intriguing set of neurodegenerative disease are the nine disorders caused by the expansion of a unstable trinucleotide CAG repeat where the repeat is located within the coding of the affected gene, that is, the polyglutamine (polyQ) diseases. A gain-of-function mechanism for toxicity in polyQ diseases is widely thought to have a major role in pathogenesis. Yet, the specific nature of this gain-of-function is a matter of considerable discussion. The basic issue concerns whether toxicity stems from the native or normal function of the affected protein versus a novel function induced by polyQ expansion. For at least three of the polyQ disease considerable evidence is accumulating that pathology is mediated by a polyQ-induced exaggeration of a native function of the host protein.
MeSH term(s)	Animals ; Autoantigens/genetics ; Autoantigens/metabolism ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Nucleus/genetics ; Cell Nucleus/metabolism ; Cilia/genetics ; Cilia/metabolism ; Glutamine/genetics ; Glutamine/metabolism ; Humans ; Huntingtin Protein ; Huntington Disease/genetics ; Huntington Disease/metabolism ; Huntington Disease/pathology ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Peptides/genetics ; Peptides/metabolism ; Phosphorylation ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism ; Spinocerebellar Ataxias/genetics ; Spinocerebellar Ataxias/metabolism ; Spinocerebellar Ataxias/pathology ; Structure-Activity Relationship ; Trinucleotide Repeat Expansion
Chemical Substances	AR protein, human ; Autoantigens ; Cell Cycle Proteins ; HTT protein, human ; Huntingtin Protein ; Nerve Tissue Proteins ; PCM1 protein, human ; Peptides ; Receptors, Androgen ; Glutamine (0RH81L854J) ; polyglutamine (26700-71-0)
Language	English
Publishing date	2012-01-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1077312-5
ISSN	1879-0380 ; 0959-437X
ISSN (online)	1879-0380
ISSN	0959-437X
DOI	10.1016/j.gde.2012.01.001
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Zs.A 3240: Show issues

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Article ; Online: SCA1-phosphorylation, a regulator of Ataxin-1 function and pathogenesis.

Orr, Harry T

Progress in neurobiology

2012 Volume 99, Issue 3, Page(s) 179–185

Abstract: Spinocerebellar ataxia type 1 (SCA1) is one an intriguing set of nine neurodegenerative diseases caused by the expansion of a unstable trinucleotide CAG repeat where the repeat is located within the coding of the affected gene, i.e. the polyglutamine ( ... ...

Abstract	Spinocerebellar ataxia type 1 (SCA1) is one an intriguing set of nine neurodegenerative diseases caused by the expansion of a unstable trinucleotide CAG repeat where the repeat is located within the coding of the affected gene, i.e. the polyglutamine (polyQ) diseases. A gain-of-function mechanism for toxicity in SCA1, like the other polyQ diseases, is thought to have a major role in pathogenesis. Yet, the specific nature of this gain-of-function is a matter of considerable discussion. An issue concerns whether toxicity stems from the native or normal function of the affected protein versus a novel function induced by polyQ expansion. For SCA1 considerable evidence is accumulating that pathology is mediated by a polyQ-induced exaggeration of a native function of the host protein Ataxin-1 (ATXN1) and that phosphorylation of S776 regulates its interaction with other cellular protein and thereby function. In addition, this posttranslational modification modulates toxicity of ATXN1 with an expanded polyglutamine.
MeSH term(s)	Animals ; Ataxin-1 ; Ataxins ; Cerebellum/metabolism ; Cerebellum/pathology ; Humans ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/metabolism ; Peptides/metabolism ; Phosphorylation/physiology ; Purkinje Cells/metabolism ; Purkinje Cells/pathology ; Spinocerebellar Ataxias/genetics ; Spinocerebellar Ataxias/metabolism ; Spinocerebellar Ataxias/pathology
Chemical Substances	ATXN1 protein, human ; Ataxin-1 ; Ataxins ; Nerve Tissue Proteins ; Nuclear Proteins ; Peptides ; polyglutamine (26700-71-0)
Language	English
Publishing date	2012-04-16
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	185535-9
ISSN	1873-5118 ; 0301-0082
ISSN (online)	1873-5118
ISSN	0301-0082
DOI	10.1016/j.pneurobio.2012.04.003
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Se 205: Show issues

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Article ; Online: Are polyglutamine diseases expanding?

Orr, Harry T

Neuron

2011 Volume 70, Issue 3, Page(s) 377–378

Abstract: It remains a matter of speculation as to whether the sense CUG-containing RNA and/or the antisense CAG-encoding polyglutamine peptide serves as the pathogenic moiety in Huntington's disease like-2 (HDL2). In this issue of Neuron, Wilburn et al. show that ...

Abstract	It remains a matter of speculation as to whether the sense CUG-containing RNA and/or the antisense CAG-encoding polyglutamine peptide serves as the pathogenic moiety in Huntington's disease like-2 (HDL2). In this issue of Neuron, Wilburn et al. show that in a HDL2 mouse model, the polyglutamine peptide drives disease progression.
Language	English
Publishing date	2011-05-12
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2011.04.015
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Zs.A 2496: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Stephen T. Warren, Ph.D. (1953-2021): A remembrance.

Nelson, David L / Clark, Janelle / Garber, Kathryn / Glover, Thomas / Hassold, Terry / Jin, Peng / Orr, Harry T / Sherman, Stephanie L / Zoghbi, Huda / Warren, Karen L

American journal of human genetics

2022 Volume 109, Issue 1, Page(s) 3–11

Language	English
Publishing date	2022-01-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2021.12.005
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