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

Abstract

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...

Loss of FBXO7 results in a Parkinson's‐like dopaminergic degeneration via an RPL23–MDM2–TP53 pathway

“…The ectopic presence of TH + cells in the striatum of the Dat Cre Fbxo7 −/fl mice, though remarkable, is not unique to this study . TH + cells occur naturally in the striatum , increasing in number following loss of nigrostriatal input in surgically lesioned animals and in transgenic mice with mutations in DA‐associated genes . They have also been observed in healthy and Parkinsonian post‐mortem human brains .…”

Large‐Scale Analysis of Redox‐Sensitive Conditionally Disordered Protein Regions Reveals Their Widespread Nature and Key Roles in High‐Level Eukaryotic Processes

“…LIM domain containing proteins have diverse biological functions, often shuttling between the nucleus and the cytoplasm, potentially even in a redox‐regulated manner, acting as adaptors or scaffolds to support the assembly of multimeric protein complexes, and can also contribute to the regulation of localization . Specifically, LMX1B controls the expression of key genes involved in mitochondrial functions . The FHL1 gene is predominantly expressed in skeletal and cardiac muscle, and its mutations are causative for several types of hereditary myopathies.…”

LIR-dependent LMX1A/LMX1B autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience

“…Long-term and tissue tissue-specific autophagy responses are controlled at the transcriptional level by diverse families of transcription factors (Fullgrabe, Ghislat et al, 2016, Fullgrabe, Klionsky et al, 2014, but the transcriptional pathways that regulate autophagy gene expression in human mDANs remain elusive. Significantly, in the conditional Lmx1a/Lmx1b knockout mice, post-mitotic mDAN functional decline was associated with dysregulated autophagy, reduced mitochondrial function, and elevated mitochondrial oxidative stress (Doucet-Beaupre et al, 2016, Laguna et al, 2015. This suggests that LMX1A/LMX1B contribute to the expression of autophagy and mitochondrial quality control genes in mDANs.…”

“…-synuclein-positive and distended axonal terminals) and behavioural abnormalities consistent with PD (Doucet-Beaupre, Gilbert et al, 2016, Laguna, Schintu et al, 2015. With this in mind, it is noteworthy that Lmx1a expression declines with age in the mouse brain (Doucet-Beaupre et al, 2016, Laguna et al, 2015, while LMX1B levels have been reported to inversely correlate with disease progression in the brains of PD patients (Laguna et al, 2015, Xia, Zhang et al, 2016. In addition, LMX1A/LMX1B polymorphisms have been linked (albeit weakly) to PD ).…”

“…Importantly, conditional knockout mouse models have unequivocally demonstrated the need for sustained Lmx1a/Lmx1b expression to support mDANs in the developed midbrain where Lmx1a/Lmx1b ablation triggered mDAN decline linked and neuropathological (e.g. -synuclein-positive and distended axonal terminals) and behavioural abnormalities consistent with PD (Doucet-Beaupre, Gilbert et al, 2016, Laguna, Schintu et al, 2015. With this in mind, it is noteworthy that Lmx1a expression declines with age in the mouse brain (Doucet-Beaupre et al, 2016, Laguna et al, 2015, while LMX1B levels have been reported to inversely correlate with disease progression in the brains of PD patients (Laguna et al, 2015, Xia, Zhang et al, 2016.…”