Age-Dependent Dopaminergic Neurodegeneration and Impairment of the Autophagy-Lysosomal Pathway in LRRK-Deficient Mice

Giaime, Emilie; Tong, Yiwei; Wagner, Lisa Katharina; Yang, Yuan; Huang, Guodong; Shen, Jie

doi:10.1016/j.neuron.2017.09.036

Cited by 105 publications

(127 citation statements)

References 51 publications

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“…As shown here, knocking out Lrrk2 and its interactor Rab29 had no significant effect on DA pathology related to PD in the aging mouse model, consistent with prior reports of single LRRK2 knockouts (Volta et al, 2015;Kuwahara et al, 2016). However, double knockout of LRRK2 and LRRK1 is reported to cause early mortality and significant DA degeneration highlighting the importance of selectively targeting LRRK2 (Giaime et al, 2017).…”

Section: Discussionsupporting

confidence: 90%

Combined knockout ofLrrk2andRab29does not result in behavioral abnormalitiesin vivo

Mazza

Nguyen

Beilina

et al. 2020

Preprint

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Coding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson's disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, leading to the suggestion that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, here we generated a double knockout mouse model and determined whether there are any consequences on brain function with aging. From a battery of motor and non-motor behavioral tests, we noted only that 18-24 month Rab29 -/and double (Lrrk2 -/-/Rab29 -/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in number of substantia nigra pars compacta (SNc) dopamine neurons or in tyrosine hydroxylase levels in the SNc and striatum, which might reflect a PD-like pathology. These results suggest that depletion of both Lrrk2 and Rab29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans. Significance statement:Genetic variation in LRRK2 that result in elevated kinase activity can cause Parkinson's disease (PD), suggesting LRRK2 inhibition as a therapeutic strategy. RAB29, a substrate of LRRK2, has also been associated with increased PD risk. Evidence exists for an interactive relationship between LRRK2 and RAB29. Mouse models lacking either LRRK2 or RAB29 do not show brain pathologies. We hypothesized that the loss of both targets would result in additive effects across in vivo and post-mortem assessments in aging mice. We found that loss of both LRRK2 and RAB29 did not result in significant behavioral deficits or dopamine neuron loss. This evidence suggests that chronic inhibition of this pathway should be tolerated clinically.

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Section: Discussionsupporting

confidence: 90%

Combined knockout ofLrrk2andRab29does not result in behavioral abnormalitiesin vivo

Mazza

Nguyen

Beilina

et al. 2020

Preprint

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“…Evidence regarding the integrity of the noradrenergic system in transgenic mice models of PD is more scarce but also stresses noradrenergic impairment. Thus, reduced tyrosine hydroxylase positive cells and a-synuclein aggregations in the LC have been demonstrated in PINK1 knockout rats (Grant et al, 2015;Cullen et al, 2018), LRRK, and parkin knockout mice (Von Coelln et al, 2004;Giaime et al, 2017). However, in transgenic mice overexpressing human A53T asynuclein, although having lower NA levels at the level of the striatum, olfactory bulb, and spinal cord, TH positive cells in the LC expressed modest a-synuclein aggregates but remained intact in number (Giasson et al, 2002;Sotiriou et al, 2010).…”

Section: Preclinical Evidencementioning

confidence: 99%

The Noradrenergic System in Parkinson’s Disease

et al. 2020

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Nowadays it is well accepted that in Parkinson's disease (PD), the neurodegenerative process occurs in stages and that damage to other areas precedes the neuronal loss in the substantia nigra pars compacta, which is considered a pathophysiological hallmark of PD. This heterogeneous and progressive neurodegeneration may explain the diverse symptomatology of the disease, including motor and non-motor alterations. In PD, one of the first areas undergoing degeneration is the locus coeruleus (LC). This noradrenergic nucleus provides extensive innervation throughout the brain and plays a fundamental neuromodulator role, participating in stress responses, emotional memory, and control of motor, sensory, and autonomic functions. Early in the disease, LC neurons suffer modifications that can condition the effectiveness of pharmacological treatments, and importantly, can lead to the appearance of common non-motor symptomatology. The noradrenergic system also exerts anti-inflammatory and neuroprotective effect on the dopaminergic degeneration and noradrenergic damage can consequently condition the progress of the disease. From the pharmacological point of view, it is also important to understand how the noradrenergic system performs in PD, since noradrenergic medication is often used in these patients, and drug interactions can take place when combining them with the gold standard drug therapy in PD, L-3,4-dihydroxyphenylalanine (L-DOPA). This review provides an overview about the functional status of the noradrenergic system in PD and its contribution to the efficacy of pharmacologicalbased treatments. Based on preclinical and clinical publications, a special attention will be dedicated to the most prevalent non-motor symptoms of the disease.

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“…What also clearly emerged from these studies is that genetic deletion of LRRK2 does not impact autophagy in the brain. A more recent study, however, revealed that the functional homolog of LRRK2, i.e., LRRK1, might play a compensatory role in LRRK2 KO mice (Giaime et al, 2017). Indeed, although any changes of autophagic markers were found in mice constitutively lacking either LRRK2 or LRRK1, double KO mice showed age-dependent increase of p62 and LC3II levels, reduction of LC3I levels, and AV accumulation, indicating an impairment of autophagy (Giaime et al, 2017).…”

Section: Rodentsmentioning

confidence: 97%

Autophagy and LRRK2 in the Aging Brain

2019

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Autophagy is a highly conserved process by which long-lived macromolecules, protein aggregates and dysfunctional/damaged organelles are delivered to lysosomes for degradation. Autophagy plays a crucial role in regulating protein quality control and cell homeostasis in response to energetic needs and environmental challenges. Indeed, activation of autophagy increases the lifespan of living organisms, and impairment of autophagy is associated with several human disorders, among which neurodegenerative disorders of aging, such as Parkinson's disease. These disorders are characterized by the accumulation of aggregates of aberrant or misfolded proteins that are toxic for neurons. Since aging is associated with impaired autophagy, autophagy inducers have been viewed as a strategy to counteract the age-related physiological decline in brain functions and emergence of neurodegenerative disorders. Parkinson's disease is a hypokinetic, multisystemic disorder characterized by agerelated, progressive degeneration of central and peripheral neuronal populations, associated with intraneuronal accumulation of proteinaceous aggregates mainly composed by the presynaptic protein α-synuclein. α-synuclein is a substrate of macroautophagy and chaperone-mediated autophagy (two major forms of autophagy), thus impairment of its clearance might favor the process of α-synuclein seeding and spreading that trigger and sustain the progression of this disorder. Genetic factors causing Parkinson's disease have been identified, among which mutations in the LRRK2 gene, which encodes for a multidomain protein encompassing central GTPase and kinase domains, surrounded by protein-protein interaction domains. Six LRRK2 mutations have been pathogenically linked to Parkinson's disease, the most frequent being the G2019S in the kinase domain. LRRK2-associated Parkinson's disease is clinically and neuropathologically similar to idiopathic Parkinson's disease, also showing age-dependency and incomplete penetrance. Several mechanisms have been proposed through which LRRK2 mutations can lead to Parkinson's disease. The present article will focus on the evidence that LRRK2 and its mutants are associated with autophagy dysregulation. Studies in cell lines and neurons in vitro and in LRRK2 knockout , knock-in, kinase-dead and transgenic animals in vivo will be reviewed. The role of aging in LRRK2-induced synucleinopathy will be discussed. Possible mechanisms underlying the LRRK2-mediated control over autophagy will be analyzed, and the contribution of autophagy dysregulation to the neurotoxic actions of LRRK2 will be examined.

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Age-Dependent Dopaminergic Neurodegeneration and Impairment of the Autophagy-Lysosomal Pathway in LRRK-Deficient Mice

Cited by 105 publications

References 51 publications

Combined knockout ofLrrk2andRab29does not result in behavioral abnormalitiesin vivo

Combined knockout ofLrrk2andRab29does not result in behavioral abnormalitiesin vivo

The Noradrenergic System in Parkinson’s Disease

Autophagy and LRRK2 in the Aging Brain

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