A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2
Since the discovery of LRRK2 mutations causal to Parkinson’s disease (PD) in the early 2000s, the LRRK2 protein has been implicated in a plethora of cellular processes in which pathogenesis could occur, yet its physiological function remains elusive. The development of genetic models of LRRK2 PD has...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-08-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnmol.2020.00153/full |
| _version_ | 1818806562755444736 |
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| author | Naila Kuhlmann Naila Kuhlmann Austen J. Milnerwood Austen J. Milnerwood |
| author_facet | Naila Kuhlmann Naila Kuhlmann Austen J. Milnerwood Austen J. Milnerwood |
| author_sort | Naila Kuhlmann |
| collection | DOAJ |
| description | Since the discovery of LRRK2 mutations causal to Parkinson’s disease (PD) in the early 2000s, the LRRK2 protein has been implicated in a plethora of cellular processes in which pathogenesis could occur, yet its physiological function remains elusive. The development of genetic models of LRRK2 PD has helped identify the etiological and pathophysiological underpinnings of the disease, and may identify early points of intervention. An important role for LRRK2 in synaptic function has emerged in recent years, which links LRRK2 to other genetic forms of PD, most notably those caused by mutations in the synaptic protein α-synuclein. This point of convergence may provide useful clues as to what drives dysfunction in the basal ganglia circuitry and eventual death of substantia nigra (SN) neurons. Here, we discuss the evolution and current state of the literature placing LRRK2 at the synapse, through the lens of knock-out, overexpression, and knock-in animal models. We hope that a deeper understanding of LRRK2 neurobiology, at the synapse and beyond, will aid the eventual development of neuroprotective interventions for PD, and the advancement of useful treatments in the interim. |
| first_indexed | 2024-12-18T19:11:45Z |
| format | Article |
| id | doaj.art-13f8a12a441c4f3d846a12df38b52ddb |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-18T19:11:45Z |
| publishDate | 2020-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-13f8a12a441c4f3d846a12df38b52ddb2022-12-21T20:56:13ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992020-08-011310.3389/fnmol.2020.00153571518A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2Naila Kuhlmann0Naila Kuhlmann1Austen J. Milnerwood2Austen J. Milnerwood3Faculty of Medicine, University of British Columbia, Vancouver, BC, CanadaDepartment of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, CanadaFaculty of Medicine, University of British Columbia, Vancouver, BC, CanadaDepartment of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, CanadaSince the discovery of LRRK2 mutations causal to Parkinson’s disease (PD) in the early 2000s, the LRRK2 protein has been implicated in a plethora of cellular processes in which pathogenesis could occur, yet its physiological function remains elusive. The development of genetic models of LRRK2 PD has helped identify the etiological and pathophysiological underpinnings of the disease, and may identify early points of intervention. An important role for LRRK2 in synaptic function has emerged in recent years, which links LRRK2 to other genetic forms of PD, most notably those caused by mutations in the synaptic protein α-synuclein. This point of convergence may provide useful clues as to what drives dysfunction in the basal ganglia circuitry and eventual death of substantia nigra (SN) neurons. Here, we discuss the evolution and current state of the literature placing LRRK2 at the synapse, through the lens of knock-out, overexpression, and knock-in animal models. We hope that a deeper understanding of LRRK2 neurobiology, at the synapse and beyond, will aid the eventual development of neuroprotective interventions for PD, and the advancement of useful treatments in the interim.https://www.frontiersin.org/article/10.3389/fnmol.2020.00153/fullParkinson’s diseaseLRRK2synapseneurotransmissiongenetic mouse modelsneuronal cultures |
| spellingShingle | Naila Kuhlmann Naila Kuhlmann Austen J. Milnerwood Austen J. Milnerwood A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2 Frontiers in Molecular Neuroscience Parkinson’s disease LRRK2 synapse neurotransmission genetic mouse models neuronal cultures |
| title | A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2 |
| title_full | A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2 |
| title_fullStr | A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2 |
| title_full_unstemmed | A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2 |
| title_short | A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2 |
| title_sort | critical lrrk at the synapse the neurobiological function and pathophysiological dysfunction of lrrk2 |
| topic | Parkinson’s disease LRRK2 synapse neurotransmission genetic mouse models neuronal cultures |
| url | https://www.frontiersin.org/article/10.3389/fnmol.2020.00153/full |
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