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17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson's disease are associated with LRRC37A/2 expression in astrocytes

Bowles, Kathryn R; Pugh, Derian A; Liu, Yiyuan; Patel, Tulsi; Renton, Alan E; Bandres-Ciga, Sara; Gan-Or, Ziv; Heutink, Peter; Siitonen, Ari; Bertelsen, Sarah; Cherry, Jonathan D; Karch, Celeste M; Frucht, Steven J; Kopell, Brian H; Peter, Inga; Park, Y J; Charney, Alexander; Raj, Towfique; Crary, John F; Goate, A M
BACKGROUND:Parkinson's disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. METHODS:To better understand the genetic contribution of this region to PD and to identify novel mechanisms conferring risk for the disease, we fine-mapped the 17q21.31 locus by constructing discrete haplotype blocks from genetic data. We used digital PCR to assess copy number variation associated with PD-associated blocks, and used human brain postmortem RNA-seq data to identify candidate genes that were then further investigated using in vitro models and human brain tissue. RESULTS:We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue. CONCLUSION/CONCLUSIONS:These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.
PMID: 35841044
ISSN: 1750-1326
CID: 5269612

A Case of Opsoclonus-Myoclonus-Ataxia With Neuronal Intermediate Filament IgG Detected in Cerebrospinal Fluid [Case Report]

Merati, Melody; Rucker, Janet C; McKeon, Andrew; Frucht, Steven J; Hu, Jessica; Balcer, Laura J; Galetta, Steven L
ABSTRACT:A 62-year-old man presented with headache, fever, and malaise. He was diagnosed with Anaplasma phagocytophilum, confirmed by serum polymerase chain reaction, and started on oral doxycycline. After 5 days of treatment, the patient began to experience gait imbalance with frequent falls, as well as myoclonus, and confusion. Examination was notable for opsoclonus-myoclonus-ataxia (OMA) and hypometric saccades. Cerebrospinal fluid (CSF) autoimmune encephalitis panel demonstrated a markedly elevated neuronal intermediate filament (NIF) immunoglobulin G antibody titer of 1:16, with positive neurofilament light- and heavy-chain antibodies. These antibodies were suspected to have been triggered by the Anaplasma infection. Repeat CSF examination 8 days later still showed a positive immunofluorescence assay for NIF antibodies, but the CSF titer was now less than 1:2. Body computed tomography imaging was unrevealing for an underlying cancer. Our patient illustrates a postinfectious mechanism for OMA and saccadic hypometria after Anaplasma infection.
PMID: 35594157
ISSN: 1536-5166
CID: 5283712

Progressive myoclonus without epilepsy due to a NUS1 frameshift insertion: Dyssynergia cerebellaris myoclonica revisited [Letter]

Monfrini, Edoardo; Miller, Claire; Frucht, Steven J; Di Fonzo, Alessio; Riboldi, Giulietta M
PMID: 35472621
ISSN: 1873-5126
CID: 5205592

Effect of Urate-Elevating Inosine on Progression of Early Parkinson Disease [Comment]

Frucht, Steven J
PMID: 34982123
ISSN: 1538-3598
CID: 5106992

Preface [Editorial]

Frucht, S J
ISSN: 2524-4043
CID: 5024082

Tardive and Neuroleptic-Induced Emergencies

Drummond, P S; Frucht, S J
Although tardive and neuroleptic-induced movement disorders are not typically viewed as neurologic emergencies, in rare instances they may manifest in ways that can produce severe bodily discomfort or even threaten vital functions like breathing and swallowing. The continued widespread use of dopamine receptor-blocking agents in the hospital and outpatient setting has necessitated their recognition, as prompt diagnosis and treatment are critical for the prevention of sometimes life-threatening complications. In this chapter, we review the history, clinical presentation, and management of neuroleptic-induced respiratory and gastrointestinal phenomena and oculogyric crisis.
ISSN: 2524-4043
CID: 5024052

A Practical Approach to Early-Onset Parkinsonism

Riboldi, Giulietta M; Frattini, Emanuele; Monfrini, Edoardo; Frucht, Steven J; Di Fonzo, Alessio
Early-onset parkinsonism (EO parkinsonism), defined as subjects with disease onset before the age of 40 or 50 years, can be the main clinical presentation of a variety of conditions that are important to differentiate. Although rarer than classical late-onset Parkinson's disease (PD) and not infrequently overlapping with forms of juvenile onset PD, a correct diagnosis of the specific cause of EO parkinsonism is critical for offering appropriate counseling to patients, for family and work planning, and to select the most appropriate symptomatic or etiopathogenic treatments. Clinical features, radiological and laboratory findings are crucial for guiding the differential diagnosis. Here we summarize the most important conditions associated with primary and secondary EO parkinsonism. We also proposed a practical approach based on the current literature and expert opinion to help movement disorders specialists and neurologists navigate this complex and challenging landscape.
PMID: 34569973
ISSN: 1877-718x
CID: 5152222

Editorial: Advances in Therapeutics for Hyperkinetic Movement Disorders [Editorial]

Klopstock, Thomas; Hall, Deborah; Frucht, Steven; Flamand-Roze, Emmanuel
PMID: 35280292
ISSN: 1664-2295
CID: 5190892

Is essential tremor a family of diseases or a syndrome? A family of diseases

Riboldi, Giulietta M; Frucht, Steven J
It is now well-established that essential tremor (ET) can manifest with different clinical presentations and progressions (i.e., upper limb tremor, head tremor, voice tremor, lower limb tremor, task- or position-specific tremor, or a combination of those). Common traits and overlaps are identifiable across these different subtypes of ET, including a slow rate of progression, a response to alcohol and a positive family history. At the same time, each of these manifestations are associated with specific demographic, clinical and treatment-response characteristics suggesting a family of diseases rather than a spectrum of a syndrome. Here we summarize the most important clinical, demographic, neuropathological and imagingfeatures of ET and of its subtypes to support ET as a family of identifiable conditions. This classification has relevance for counseling of patients with regard to disease progression and treatment response, as well as for the design of therapeutic clinical trials.
PMID: 35750371
ISSN: 2162-5514
CID: 5268812

Dysregulation of mitochondrial and proteolysosomal genes in Parkinson's disease myeloid cells

Navarro, Elisa; Udine, Evan; de Paiva Lopes, Katia; Parks, Madison; Riboldi, Giulietta; Schilder, Brian M; Humphrey, Jack; Snijders, Gijsje J L; Vialle, Ricardo A; Zhuang, Maojuan; Sikder, Tamjeed; Argyrou, Charalambos; Allan, Amanda; Chao, Michael J; Farrell, Kurt; Henderson, Brooklyn; Simon, Sarah; Raymond, Deborah; Elango, Sonya; Ortega, Roberto A; Shanker, Vicki; Swan, Matthew; Zhu, Carolyn W; Ramdhani, Ritesh; Walker, Ruth H; Tse, Winona; Sano, Mary; Pereira, Ana C; Ahfeldt, Tim; Goate, Alison M; Bressman, Susan; Crary, John F; de Witte, Lotje; Frucht, Steven; Saunders-Pullman, Rachel; Raj, Towfique
An increasing number of identified Parkinson's disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their role in pathology is not understood. We hypothesize that PD susceptibility genes modulate disease risk by influencing gene expression within immune cells. To address this, we have generated transcriptomic profiles of monocytes from 230 individuals with sporadic PD and healthy subjects. We observed a dysregulation of mitochondrial and proteasomal pathways. We also generated transcriptomic profiles of primary microglia from brains of 55 subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified 17 PD susceptibility genes whose expression, relative to each risk allele, is altered in monocytes. These findings reveal widespread transcriptomic alterations in PD monocytes, with some being distinct from microglia, and facilitate efforts to understand the roles of myeloid cells in PD as well as the development of biomarkers.
PMID: 35005630
ISSN: 2662-8465
CID: 5118342