Ventral midbrain dopaminergic neurons: From neurogenesis to neurodegeneration

Abstract

Ventral midbrain dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc, A9 group), ventral tegmental area (VTA, A10 group) and the retrorubral field (RRF, A8 group) are a group of closely related neurons that share developmental profiles and origin. The neural circuits established by DA neurons include the nigrostriatal pathway that connects SNpc with the striatum, the mesolimbic pathway that connects DA neurons in VTA with the nucleus accumbens (NAc) and the limbic systems, and the mesocortical pathway that connect VTA neurons with the prefrontal cortex (Fig. 1 ). Collectively, these neural circuits defined by DA neurons play an essential role in motor control, reward behaviors and habit learning. This FEBS Letters Special Issue provides a comprehensive review on several important topics regarding DA neurons, including the molecular mechanisms that regulate the establishment, diversification, and survival of DA neurons, the mechanisms that govern the formation of functional DA neural circuits, and how mitochondrial abnormalities and α-synuclein protein misfolding contribute to the degeneration of DA neurons. To address the mechanisms that determine cell fate specification, progenitor expansion and differentiation of DA neurons, Doucet-Beaupré and colleagues focus on two highly evolutionarily conserved LIM homeodomain transcription factors, Lmx1a and Lmx1b, and their role in the establishment of the DA progenitor domain in the isthmic organizer in the ventral midbrain during early embryonic development [1]. The authors summarize the transcriptional targets of Lmx1a and Lmx1b, including the autoregulatory feedback loop between Wnt1 and Lmx1b. Following the discussion on Lmx1a and Lmx1b, Bodea and Blaess summarize how transcription factors and exogenous factors, such as Wnt's, sonic hedgehog (Shh), and axon guidance molecules, provide both cell intrinsic and extrinsic cues to regulate the development of DA progenitors and DA neurons [2]. To understand the diversity and heterogeneity in DA neurons, Andreregg and colleagues review recent evidence that DA neurons are not a homogeneous group of neurons [3]. Indeed, results from single cell transcriptome analyses provide compelling evidence that DA neurons in distinct anatomical locations in SNpc and VTA are endowed with molecular characteristics that support their distinct physiological and functional properties. Finally, Morello and Partanen discuss the development and integration of GABAergic neurons into the neural circuits established by the DA neurons [4]. Their article highlights the emerging appreciation of a holistic approach to investigate DA neurons in the context of circuit functions. In particular, the identification of both local GABAergic inhibitory neurons in SNpr, RMTg (retromedial tegmental nucleus) and VTA, and excitatory neurons near DA neurons provides important framework for future studies to elucidate additional mechanisms that control the assembly, connectivity, maintenance and degeneration in the important neural circuits established by DA neurons. To understand the mechanisms that support the survival of DA neurons, Kramer and Liss discuss the expression of GDNF receptors c-Ret and GFRα1 in DA neurons during development and in postnatal life [5]. In addition, they summarize their recent discovery that removal of c-Ret affects the maintenance of mature DA neurons during the aging process via the pro-survival phosphoinositide-3-kinase (PI3K)-NFκB pathway and Parkin-dependent regulation of mitochondrial functions [6]. These results reveal previously unrecognized roles of GDNF-c-Ret signaling in the maintenance of DA neurons during neurodegeneration, and suggest the presence of additional trophic factors that could support the survival and functions of DA neurons in perinatal and early postnatal stages. In addition to GDNF-Ret signaling pathways, Voutilainen and colleagues review the role of two neurotrophic factors, CDNF (cerebral DA neurotrophic factor) and MANF (mesencephalic astrocyte-derived neurotrophic factor), in DA neurons [7]. Unlike NGF and BDNF, CDNF and MANF have unconventional properties in protecting neurodegeneration induced by ER stress and neurotoxins [8-10]. These results support the idea that CDNF and MANF could potentially protect DA neurons from neurodegenerative conditions, such as Parkinson's disease. Finally, the article by Rekaik and colleagues focuses on the rather unique mechanism of two closely related homeoproteins, Engrailed-1 and Engrailed-2 (En1/2), for the survival of DA neurons [11]. En1/2 is required for the proper development of DA neurons during the embryonic stage. However, En1 heterozygous mice show age-dependent progressive loss of DA neurons [12, 13]. The neuroprotective effects of En1 are due in part to the ability of En1/2 in regulating the translation of mitochondrial mRNA for subunits in complex I and other transcription factors that are critical for the development of DA neurons [14]. Finally, progressive loss of DA neurons is a well-recognized feature in Parkinson's disease (PD), the second most common neurodegenerative disease [15]. A key neuropathological feature of PD is the presence of misfolded α-synuclein proteins inside the cell body and processes of DA neurons, which is also known as Lewy body pathology [16]. The article by Luna and Luk summarizes the mechanisms leading to the formation of α-synuclein protein aggregates [17]. They discuss the identification of “prion-like” properties that enable the misfolded α-synuclein fibrils to propagate within the nervous system in a circuit-dependent manner, and the potential mechanisms that allow neurons to become permissive to α-synuclein protein propagation. They also highlight several important cellular stress conditions, including ER stress, oxidative stress and neuroinflammation, which are induced by the misfolded α-synuclein proteins. While the majority of PD cases are sporadic, about 15% of PD cases have genetic mutations that contribute to the neurodegeneration in DA neurons [18]. Recent studies have provided compelling evidence that several PD genes are implicated in the quality control of mitochondrial functions. In their article, Haddad and Nakamura review the mechanisms by which mitochondrial toxins cause degeneration in DA neurons [19]. They then highlight the important functions of several PD genes, including PINK1, Parkin, DJ-1, and LRRK2, in regulating mitochondrial turnover (mitophagy), complex I function, mitochondrial dynamics and transport. Finally, they put together a strong argument that supports the central role of mitochondria in the maintenance of neuronal survival. Together, these stimulating discussions provide important insight to the understanding of α-synuclein pathology and mitochondrial functions in the pathophysiology of PD. Ventral midbrain dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc, A9 group), ventral tegmental area (VTA, A10 group) and the retrorubral field (RRF, A8 group) are a group of closely related neurons that share developmental profiles and origin. The neural circuits established by DA neurons include the nigrostriatal pathway that connects SNpc with the striatum, the mesolimbic pathway that connects DA neurons in VTA with the nucleus accumbens (NAc) and the limbic systems, and the mesocortical pathway that connect VTA neurons with the prefrontal cortex (Fig. 1 ). Collectively, these neural circuits defined by DA neurons play an essential role in motor control, reward behaviors and habit learning. This FEBS Letters Special Issue provides a comprehensive review on several important topics regarding DA neurons, including the molecular mechanisms that regulate the establishment, diversification, and survival of DA neurons, the mechanisms that govern the formation of functional DA neural circuits, and how mitochondrial abnormalities and α-synuclein protein misfolding contribute to the degeneration of DA neurons. To address the mechanisms that determine cell fate specification, progenitor expansion and differentiation of DA neurons, Doucet-Beaupré and colleagues focus on two highly evolutionarily conserved LIM homeodomain transcription factors, Lmx1a and Lmx1b, and their role in the establishment of the DA progenitor domain in the isthmic organizer in the ventral midbrain during early embryonic development [1]. The authors summarize the transcriptional targets of Lmx1a and Lmx1b, including the autoregulatory feedback loop between Wnt1 and Lmx1b. Following the discussion on Lmx1a and Lmx1b, Bodea and Blaess summarize how transcription factors and exogenous factors, such as Wnt's, sonic hedgehog (Shh), and axon guidance molecules, provide both cell intrinsic and extrinsic cues to regulate the development of DA progenitors and DA neurons [2]. To understand the diversity and heterogeneity in DA neurons, Andreregg and colleagues review recent evidence that DA neurons are not a homogeneous group of neurons [3]. Indeed, results from single cell transcriptome analyses provide compelling evidence that DA neurons in distinct anatomical locations in SNpc and VTA are endowed with molecular characteristics that support their distinct physiological and functional properties. Finally, Morello and Partanen discuss the development and integration of GABAergic neurons into the neural circuits established by the DA neurons [4]. Their article highlights the emerging appreciation of a holistic approach to investigate DA neurons in the context of circuit functions. In particular, the identification of both local GABAergic inhibitory neurons in SNpr, RMTg (retromedial tegmental nucleus) and VTA, and excitatory neurons near DA neurons provides important framework for future studies to elucidate additional mechanisms that control the assembly, connectivity, maintenance and degeneration in the important neural circuits established by DA neurons. To understand the mechanisms that support the survival of DA neurons, Kramer and Liss discuss the expression of GDNF receptors c-Ret and GFRα1 in DA neurons during development and in postnatal life [5]. In addition, they summarize their recent discovery that removal of c-Ret affects the maintenance of mature DA neurons during the aging process via the pro-survival phosphoinositide-3-kinase (PI3K)-NFκB pathway and Parkin-dependent regulation of mitochondrial functions [6]. These results reveal previously unrecognized roles of GDNF-c-Ret signaling in the maintenance of DA neurons during neurodegeneration, and suggest the presence of additional trophic factors that could support the survival and functions of DA neurons in perinatal and early postnatal stages. In addition to GDNF-Ret signaling pathways, Voutilainen and colleagues review the role of two neurotrophic factors, CDNF (cerebral DA neurotrophic factor) and MANF (mesencephalic astrocyte-derived neurotrophic factor), in DA neurons [7]. Unlike NGF and BDNF, CDNF and MANF have unconventional properties in protecting neurodegeneration induced by ER stress and neurotoxins [8-10]. These results support the idea that CDNF and MANF could potentially protect DA neurons from neurodegenerative conditions, such as Parkinson's disease. Finally, the article by Rekaik and colleagues focuses on the rather unique mechanism of two closely related homeoproteins, Engrailed-1 and Engrailed-2 (En1/2), for the survival of DA neurons [11]. En1/2 is required for the proper development of DA neurons during the embryonic stage. However, En1 heterozygous mice show age-dependent progressive loss of DA neurons [12, 13]. The neuroprotective effects of En1 are due in part to the ability of En1/2 in regulating the translation of mitochondrial mRNA for subunits in complex I and other transcription factors that are critical for the development of DA neurons [14]. Finally, progressive loss of DA neurons is a well-recognized feature in Parkinson's disease (PD), the second most common neurodegenerative disease [15]. A key neuropathological feature of PD is the presence of misfolded α-synuclein proteins inside the cell body and processes of DA neurons, which is also known as Lewy body pathology [16]. The article by Luna and Luk summarizes the mechanisms leading to the formation of α-synuclein protein aggregates [17]. They discuss the identification of “prion-like” properties that enable the misfolded α-synuclein fibrils to propagate within the nervous system in a circuit-dependent manner, and the potential mechanisms that allow neurons to become permissive to α-synuclein protein propagation. They also highlight several important cellular stress conditions, including ER stress, oxidative stress and neuroinflammation, which are induced by the misfolded α-synuclein proteins. While the majority of PD cases are sporadic, about 15% of PD cases have genetic mutations that contribute to the neurodegeneration in DA neurons [18]. Recent studies have provided compelling evidence that several PD genes are implicated in the quality control of mitochondrial functions. In their article, Haddad and Nakamura review the mechanisms by which mitochondrial toxins cause degeneration in DA neurons [19]. They then highlight the important functions of several PD genes, including PINK1, Parkin, DJ-1, and LRRK2, in regulating mitochondrial turnover (mitophagy), complex I function, mitochondrial dynamics and transport. Finally, they put together a strong argument that supports the central role of mitochondria in the maintenance of neuronal survival. Together, these stimulating discussions provide important insight to the understanding of α-synuclein pathology and mitochondrial functions in the pathophysiology of PD.