Dopaminergic control of autophagic-lysosomal function implicates Lmx1b in Parkinson's disease

Laguna, Ariadna; Schintu, Nicoletta; Nobre, André; Alvarsson, Alexandra; Volakakis, Nikolaos; Jacobsen, Jesper Kjaer; Gómez-Galán, Marta; Sopova, Elena; Joodmardi, Eliza; Yoshitake, Takashi; Deng, Qiaolin; Kehr, Ján; Ericson, Johan; Svenningsson, Per; Shupliakov, Oleg; Perlmann, Thomas

doi:10.1038/nn.4004

Cited by 69 publications

(105 citation statements)

References 364 publications

(389 reference statements)

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“…1C and Fig. S1) were still detectable in aged (13-mo-old) mice, supporting previous reports (12)(13)(14).…”

Section: Resultssupporting

confidence: 91%

“…A recent study reported that removal of Lmx1b in postnatal mDa neurons produced enlarged axon terminals associated with an alteration in autophagic flux (13). We also observed modification of the LC3-II protein level in 2-mo-old Lmx1a/b cKO mice, supporting the idea that the autophagic flux is altered in these mice.…”

Section: Discussionsupporting

confidence: 87%

“…Evidence suggests the involvement of autophagy deregulation in PD, and a recent study reported that removal of Lmx1b in postnatal mDA neurons produced enlarged axon terminals associated with an alteration in autophagy (13). In 2-mo-old Lmx1a/b cKO mice, we measured and confirmed a significant change in LC3-II at the protein level ( Fig.…”

Section: Lmx1a/b Mutant Cells Exhibit Overproduction Of Reactive Oxygensupporting

confidence: 74%

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Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

Doucet-Beaupré

Gilbert

Profes

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The LIM-homeodomain transcription factors Lmx1a and Lmx1b play critical roles during the development of midbrain dopaminergic progenitors, but their functions in the adult brain remain poorly understood. We show here that sustained expression of Lmx1a and Lmx1b is required for the survival of adult midbrain dopaminergic neurons. Strikingly, inactivation of Lmx1a and Lmx1b recreates cellular features observed in Parkinson's disease. We found that Lmx1a/b control the expression of key genes involved in mitochondrial functions, and their ablation results in impaired respiratory chain activity, increased oxidative stress, and mitochondrial DNA damage. Lmx1a/b deficiency caused axonal pathology characterized by α-synuclein + inclusions, followed by a progressive loss of dopaminergic neurons. These results reveal the key role of these transcription factors beyond the early developmental stages and provide mechanistic links between mitochondrial dysfunctions, α-synuclein aggregation, and the survival of dopaminergic neurons. M idbrain dopaminergic (mDA) neurons control key functions in the mammalian brain, including voluntary movement, associative learning, and motivated behaviors. Dysfunctions of the dopaminergic (DA) system underlie a wide variety of neurological and psychiatric disorders. The progressive and rather selective degeneration of mDA neurons is one of the principal pathological features of Parkinson's disease (PD) (1). In PD, neuronal loss is accompanied by the appearance of α-synucleinenriched intraneuronal inclusions called "Lewy bodies" and "Lewy neurites." The etiologies of PD remain unsolved, but mitochondrial dysfunction emerges as a central mechanism in inherited, sporadic, and toxin-induced PD (2).Specification of the subtype identities of mDA neurons begins during embryonic development. The combinatory activation of transcription factors (TFs) and their target genes allows the progenitors to mature progressively and terminally differentiate into postmitotic neuron subtypes. Tremendous efforts have been made to describe the complex spatiotemporal expression of TFs during mDA neuronal development (see refs. 3 and 4 for reviews). After mDA neuron maturation, a large number of developmentally expressed TFs remain active throughout adulthood. Our knowledge of the functional roles of these TFs in mature neurons remains rudimentary. Accumulating evidence shows that transcription factors including the nuclear receptor related 1 protein (Nurr1), En1, Pitx3, Otx2, and Foxa2, which are recognized for their role in the early development of mDA neurons, are also required for the maintenance of phenotypic neuronal identity in the adult (5).The LIM homeodomain genes Lmx1a/b are early determinants of the fate of mDA progenitors (6), and their actions are essential at each step of DA neuronal generation (7,8). The murine Lmx1a and Lmx1b proteins are closely related and share an overall amino acid identity of 64%, with 100% identity in their homeodomain and 67% and 83% identity in each LIM domain (9). These neuron...

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“…1C and Fig. S1) were still detectable in aged (13-mo-old) mice, supporting previous reports (12)(13)(14).…”

Section: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 87%

Section: Lmx1a/b Mutant Cells Exhibit Overproduction Of Reactive Oxygensupporting

confidence: 74%

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Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

Doucet-Beaupré

Gilbert

Profes

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…All of them present some form of axonal abnormalities in TH-positive nigrostriatal fibers before the degenerative processes are detected in the cell bodies. Interestingly, very similar manifestation of early axonopathy is present in all of them: 'swollen' structures called 'spheroids' or 'axonal swellings' appearing in the terminal parts [10,11,13,15,17] or medial forebrain bundle portions of nigrostriatal axons [12,14,15]. Similar axonal spheroids were described in the post-mortem brains of PD [18] and Diffuse Lewy Body Disease patients [19], and they are also seen in other neurodegenerative diseases such as multiple sclerosis (MS).…”

Section: Main Textmentioning

confidence: 82%

Is Axonal Degeneration a Key Early Event in Parkinson’s Disease?

Kurowska

Kordower

Stoessl

et al. 2016

JPD

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Recent research suggests that in Parkinson's disease the long, thin and unmyelinated axons of dopaminergic neurons degenerate early in the disease process. We organized a workshop entitled 'Axonal Pathology in Parkinson's disease', on March 23 rd , 2016, in Cleveland, Ohio with the goals of summarizing the state-of-the-art and defining key gaps in knowledge. A group of eight research leaders discussed new developments in clinical pathology, functional imaging, animal models, and mechanisms of degeneration including neuroinflammation, autophagy and axonal transport deficits. While the workshop focused on PD, comparisons were made to other neurological conditions where axonal degeneration is well recognized. Main textAround 7 -10 million people worldwide suffer from Parkinson's disease (PD). PD is usually diagnosed based on motor symptoms (e.g. tremor, slowness of movements, bradykinesia) which are attributed to loss of dopamine in the striatum, as a consequence to degeneration of nigrostriatal dopamine neurons. Devising methods to protect the cell bodies of nigral dopamine neurons has long been a research priority, but emerging knowledge suggests that the research community should shift its focus from the soma to the axonal compartment of dopaminergic neurons.'I had been sitting on these data for two years before I submitted the paper' -said Dr. Jeffrey Kordower in the first talk of the Workshop, referring to his initial skepticism about the finding published in 2013 that in brains of PD patients, only 3-7 years after the diagnosis the putamen is almost completely depleted of TH-positive axons, while numerous cell bodies in the SNpc remain because the death of these neurons occurs at much slower pace [1]. It is not known if the axons had already degenerated at 3-7 years after diagnosis, or they are still there, just not expressing TH and other molecules involved in production and maintenance of functional dopaminergic synapses. Unfortunately, it has not been possible to address those questions in post-mortem human brains, as a structural marker specific for dopaminergic axons is not available, and striatum is innervated by axons from multiple nuclei including the cortex, amygdala, and raphe.Dr. Kordower also highlighted that studies with the growth factors GDNF/neurturin in monkeys and PD patients have suggested that nigrostriatal pathway axons need to be preserved for functional recovery to occur [2,3]. Moreover, the restoration of the nigrostriatal pathway alone is not necessarily translated to functional benefits as formation of synapses with the right target is also required.Degenerative changes that eventually lead to PD diagnosis start several years before the disease is discovered, and it is possible that loss of synaptic function in dopaminergic neurons is one of the first changes. Dr. Jon Stoessl presented the functional imaging data from PD patients showing evidence for early changes in striatal dopaminergic terminals [4]. The changes in effective dopamine turnover in the caudate and the putamen...

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“…For example, conditional knockout (cKO) of Lmx1b has been associated with perturbations in the ALP (Laguna et al, 2015). Lmx1b is involved in postmitotic neuronal regulation of ALP proteins Beclin1, Lamp1-2, p62, cathepsin D and LC3BI-II.…”

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confidence: 99%

Malfunctions in synaptic membrane trafficking in early pathology of Parkinson’s disease: New molecular clues

Sopova¹,

Korenkova²,

Shupliakov³

2017

BioComm

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The midbrain dopaminergic neurons of the substantia nigra and the ventral tegmental area play vital roles in the regulation of voluntary movement, emotion and reward in humans. These neurons are highly metabolic and are under constant oxidative stress. The dopaminergic neurons form extensive synaptic projections to the striatum. When these neurons start dying or when their synaptic connections fail, humans develop Parkinson´s disease. This disease is accompanied by the accumulation of toxic α-synuclein-containing protein aggregates in nigrostriatal processes. Synucleins accumulate in a majority of healthy nerve terminals in the central nervous system, but what causes the formation of pathological synuclein aggregates is unclear. Recent studies point out that the interface between membrane trafficking in the nerve terminal and the autophagy-lysosomal pathway is the site for the aggregate assembly. An urgent goal is to find therapeutic targets at early stages of the disease when neurons are still functional.

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Dopaminergic control of autophagic-lysosomal function implicates Lmx1b in Parkinson's disease

Cited by 69 publications

References 364 publications

Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

Is Axonal Degeneration a Key Early Event in Parkinson’s Disease?

Malfunctions in synaptic membrane trafficking in early pathology of Parkinson’s disease: New molecular clues

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