199 years of Parkinson disease – what have we learned and what is the path to the future?

Schulz, Jörg B.; Hausmann, Laura; Hardy, John

doi:10.1111/jnc.13733

Cited by 18 publications

(15 citation statements)

References 54 publications

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“…Mutations in leucine rich repeat kinase 2 (LRRK2) are a major cause of familial and sporadic Parkinson's Disease (PD), a neurodegenerative disease characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) region of the midbrain (Cookson, 2017;Kim and Alcalay, 2017;Martin et al, 2014;Schulz et al, 2016). Despite LRRK2 having been implicated in a variety of cellular processes including cytoskeletal dynamics (Civiero et al, 2018;Kett et al, 2012;Pellegrini et al, 2017), vesicular trafficking (Herbst and Gutierrez, 2019;Sanna et al, 2012;Shi et al, 2017), calcium signaling (Bedford et al, 2016;Calì et al, 2014), and mitochondrial function (Ryan et al, 2015;Singh et al, 2019;Yue et al, 2015), its precise mechanistic contributions to triggering and/or exacerbating PD and other disease pathologies are not known.…”

Section: Introductionmentioning

confidence: 99%

LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

Weindel

Bell

Vail

et al. 2020

eLife

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The Parkinson’s disease (PD)-associated gene leucine-rich repeat kinase 2 (LRRK2) has been studied extensively in the brain. However, several studies have established that mutations in LRRK2 confer susceptibility to mycobacterial infection, suggesting LRRK2 also controls immunity. We demonstrate that loss of LRRK2 in macrophages induces elevated basal levels of type I interferon (IFN) and interferon stimulated genes (ISGs) and causes blunted interferon responses to mycobacterial pathogens and cytosolic nucleic acid agonists. Altered innate immune gene expression in Lrrk2 knockout (KO) macrophages is driven by a combination of mitochondrial stresses, including oxidative stress from low levels of purine metabolites and DRP1-dependent mitochondrial fragmentation. Together, these defects promote mtDNA leakage into the cytosol and chronic cGAS engagement. While Lrrk2 KO mice can control Mycobacterium tuberculosis (Mtb) replication, they have exacerbated inflammation and lower ISG expression in the lungs. These results demonstrate previously unappreciated consequences of LRRK2-dependent mitochondrial defects in controlling innate immune outcomes.

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Section: Introductionmentioning

confidence: 99%

LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

Weindel

Bell

Vail

et al. 2020

eLife

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“…Parkinson’s disease (PD) is the second most common neurodegenerative disease (Schulz et al, 2016; Obeso et al, 2017). Its motor-related symptoms are caused by a progressive loss of dopaminergic (DA) neurons, particularly within the Substantia nigra (SN) (Damier et al, 1999; Surmeier et al, 2017b; Giguere et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

NCS-1 Deficiency Affects mRNA Levels of Genes Involved in Regulation of ATP Synthesis and Mitochondrial Stress in Highly Vulnerable Substantia nigra Dopaminergic Neurons

Simons

Benkert

Deuter

et al. 2019

Front. Mol. Neurosci.

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Neuronal Ca2+ sensor proteins (NCS) transduce changes in Ca2+ homeostasis into altered signaling and neuronal function. NCS-1 activity has emerged as important for neuronal viability and pathophysiology. The progressive degeneration of dopaminergic (DA) neurons, particularly within the Substantia nigra (SN), is the hallmark of Parkinson’s disease (PD), causing its motor symptoms. The activity-related Ca2+ homeostasis of SN DA neurons, mitochondrial dysfunction, and metabolic stress promote neurodegeneration and PD. In contrast, NCS-1 in general has neuroprotective effects. The underlying mechanisms are unclear. We analyzed transcriptional changes in SN DA neurons upon NCS-1 loss by combining UV-laser microdissection and RT-qPCR-approaches to compare expression levels of a panel of PD and/or Ca2+-stress related genes from wildtype and NCS-1 KO mice. In NCS-1 KO, we detected significantly lower mRNA levels of mitochondrially coded ND1, a subunit of the respiratory chain, and of the neuron-specific enolase ENO2, a glycolytic enzyme. We also detected lower levels of the mitochondrial uncoupling proteins UCP4 and UCP5, the PARK7 gene product DJ-1, and the voltage-gated Ca2+ channel Cav2.3 in SN DA neurons from NCS-1 KO. Transcripts of other analyzed uncoupling proteins (UCPs), mitochondrial Ca2+ transporters, PARK genes, and ion channels were not altered. As Cav channels are linked to regulation of gene expression, metabolic stress and degeneration of SN DA neurons in PD, we analyzed Cav2.3 KO mice, to address if the transcriptional changes in NCS-1 KO were also present in Cav.2.3 KO, and thus probably correlated with lower Cav2.3 transcripts. However, in SN DA neurons from Cav2.3 KO mice, ND1 mRNA as well as genomic DNA levels were elevated, while ENO2, UCP4, UCP5, and DJ-1 transcript levels were not altered. In conclusion, our data indicate a possible novel function of NCS-1 in regulating gene transcription or stabilization of mRNAs in SN DA neurons. Although we do not provide functional data, our findings at the transcript level could point to impaired ATP production (lower ND1 and ENO2) and elevated metabolic stress (lower UCP4, UCP5, and DJ-1 levels) in SN DA neurons from NCS-1 KO mice. We speculate that NCS-1 is involved in stimulating ATP synthesis, while at the same time controlling mitochondrial metabolic stress, and in this way could protect SN DA neurons from degeneration.

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“…In PD patients, constipation is at least three times as prevalent as it is among the general population [47], and several researchers believe that constipation is a universal feature of PD [48]. In both PD and NCDLB, the symptom of bowel immotility often presents years before other diagnostic features [47,[49][50][51][52][53] sometimes as much as 20 years before the emergence of others symptoms leading to the diagnosis of PD or NCDLB [17]. This occurs so frequently that many experts suggest that bowel immotility is a prodromal symptom for both PD and NCDLB [17,21,25,37,[54][55][56][57].…”

Section: Symptomatic Manifestations Of α-Synuclein Pathology In the Ensmentioning

confidence: 99%

Prevalence and Treatment of Constipation in Patients with Alpha-Synuclein Pathology

Lepkowsky¹

2019

Constipation

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α-Synuclein "Lewy body" pathology is the basis of Parkinson's disease (PD) and neurocognitive disorder with Lewy bodies (NCDLB), sometimes called Lewy body dementia. In patients with α-synuclein pathology, constipation, obstipation and impaction are almost universal symptoms, whose treatment represents a significant burden on health care economies. Description is given of the specific mechanisms through which α-synuclein pathology induces these symptoms, and through which the use of acetylcholinesterase inhibitors (AChEIs) might significantly reduce them. Four case studies are presented testing the hypothesis that the use of the cholinergic agonist donepezil might reduce the symptom of constipation in four patients with NCDLB or PD at different stages of disease progression. Outcomes are presented, as well as follow-up data at 6-, 12-, and 18-month intervals. The potential use of donepezil to reduce the symptoms of constipation in patients with α-synuclein pathology is discussed.

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199 years of Parkinson disease – what have we learned and what is the path to the future?

Cited by 18 publications

References 54 publications

LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

NCS-1 Deficiency Affects mRNA Levels of Genes Involved in Regulation of ATP Synthesis and Mitochondrial Stress in Highly Vulnerable Substantia nigra Dopaminergic Neurons

Prevalence and Treatment of Constipation in Patients with Alpha-Synuclein Pathology

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