Peripheral administration of the Class-IIa HDAC inhibitor MC1568 partially protects against nigrostriatal neurodegeneration in the striatal 6-OHDA rat model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterised by nigrostriatal dopaminergic (DA) neurodegeneration. There is a critical need for neuroprotective therapies, particularly those that do not require direct intracranial administration. Small molecule inhibitors of histone deacetylases (HDIs) are neuroprotective in in vitro and in vivo models of PD, however it is unknown whether Class IIa-specific HDIs are neuroprotective when administered peripherally. Here we show that 6-hydroxydopamine (6-OHDA) treatment induces protein kinase C (PKC)-dependent nuclear accumulation of the Class IIa histone deacetylase (HDAC)5 in SH-SY5Y cells and cultured DA neurons in vitro. Treatment of these cultures with the Class IIa-specific HDI, MC1568, partially protected against 6-OHDA-induced cell death. In the intrastriatal 6-OHDA lesion in vivo rat model of PD, MC1568 treatment (0.5 mg/kg i.p.) for 7 days reduced forelimb akinesia and partially protected DA neurons in the substantia nigra and their striatal terminals from 6-OHDA-induced neurodegeneration. MC1568 treatment prevented 6-OHDA-induced increases in microglial activation in the striatum and substantia nigra. Furthermore, MC1568 treatment decreased 6-OHDA-induced increases in nuclear HDAC5 in nigral DA neurons. These data suggest that peripheral administration of Class IIa-specific HDIs may be a potential therapy for neuroprotective in PD.

LMK235, a small molecule inhibitor of HDAC4/5, protects dopaminergic neurons against neurotoxin- and α-synuclein-induced degeneration in cellular models of Parkinson's disease.

Epigenetic modifications in neurodegenerative disease are under investigation for their roles in disease progression. Alterations in acetylation rates of certain Parkinson's disease (PD)-linked genes have been associated with the pathological progression of this disorder. In light of this, and given the lack of disease-modifying therapies for PD, HDAC inhibitors (HDIs) are under consideration as potential pharmacological agents. The neuroprotective effects of pan-HDACs and some class-specific inhibitors have been tested in in vivo and in vitro models of PD, with varying outcomes. Here we used gene co-expression analysis to identify HDACs that are associated with human dopaminergic (DA) neuron development. We identified HDAC3, HDAC5, HDAC6 and HDAC9 as being highly correlated with the DA markers, SLC6A3 and NR4A2. RT-qPCR revealed that mRNA expression of these HDACs exhibited similar temporal profiles during embryonic mouse midbrain DA (mDA) neuron development. We tested the neuroprotective potential of a number of class-specific small molecule HDIs on human SH-SY5Y cells, using neurite growth as a phenotypic readout of neurotrophic action. Neither the class I-specific HDIs, RGFP109 and RGFP966, nor the HDAC6 inhibitor ACY1215, had significant effects on neurite outgrowth. However, the class IIa HDI, LMK235 (a HDAC4/5 inhibitor), significantly increased histone acetylation and neurite outgrowth. We found that LMK235 increased BMP-Smad-dependent transcription in SH-SY5Y cells and that this was required for its neurite growth-promoting effects on SH-SY5Y cells and on DA neurons in primary cultures of embryonic day (E) 14 rat ventral mesencephalon (VM). These effects were also seen in SH-SY5Y cells transfected with HDAC5 siRNA. Furthermore, LMK235 treatment exerted neuroprotective effects against degeneration induced by the DA neurotoxin 1-methyl-4-phenylpyridinium (MPP+), in both SH-SY5Y cells and cultured DA neurons. Treatment with LMK235 was also neuroprotective against axonal degeneration induced by overexpression of wild-type (WT) or A53T mutant α-synuclein in both SH-SY5Y cells and primary cultures of DA neurons. In summary, these data show the neuroprotective potential of the class IIa HDI, LMK235, in cell models of relevance to PD.

The Parkinson's disease gene PINK1 activates Akt via PINK1 kinase-dependent regulation of the phospholipid PI(3,4,5)P3.

Akt signalling is central to cell survival, metabolism, protein and lipid homeostasis, and is impaired in Parkinson's disease (PD). Akt activation is reduced in the brain in PD, and by many PD-causing genes, including PINK1 This study investigated the mechanisms by which PINK1 regulates Akt signalling. Our results reveal for the first time that PINK1 constitutively activates Akt in a PINK1-kinase dependent manner in the absence of growth factors, and enhances Akt activation in normal growth medium. In PINK1-modified MEFs, agonist-induced Akt signalling failed in the absence of PINK1, due to PINK1 kinase-dependent increases in PI(3,4,5)P3 at both plasma membrane and Golgi being significantly impaired. In the absence of PINK1, PI(3,4,5)P3 levels did not increase in the Golgi, and there was significant Golgi fragmentation, a recognised characteristic of PD neuropathology. PINK1 kinase activity protected the Golgi from fragmentation in an Akt-dependent fashion. This study demonstrates a new role for PINK1 as a primary upstream activator of Akt via PINK1 kinase-dependent regulation of its primary activator PI(3,4,5)P3, providing novel mechanistic information on how loss of PINK1 impairs Akt signalling in PD.This article has an associated First Person interview with the first author of the paper.

Trophic factors for Parkinson's disease: Where are we and where do we go from here?

Perhaps the most important unmet clinical need in Parkinson's disease (PD) is the development of a therapy that can slow or halt disease progression. Extensive preclinical research has provided evidence for the neurorestorative properties of several growth factors, yet only a few have been evaluated in clinical studies. Attempts to achieve neuroprotection by addressing cell-autonomous mechanisms and targeting dopaminergic neurons have been disappointing. Four different trophic factors have so far entered clinical trials in PD: glial cell line-derived growth factor, its close structural and functional analog neurturin, platelet-derived growth factor and cerebral dopaminergic neurotrophic factor. This article reviews the pre-clinical evidence for the neuroprotective and neurorestorative actions of these growth factors and discusses limitations of preclinical models, which may hamper successful translation to the clinic. We summarize the previous and ongoing clinical trials using growth factors in PD and emphasize the caveats in clinical trial design that may prevent the further development and registration of potentially neuroprotective and neurorestorative treatments for individuals suffering from PD.

Distinct alterations in motor & reward seeking behavior are dependent on the gestational age of exposure to LPS-induced maternal immune activation.

The dopaminergic system is involved in motivation, reward and the associated motor activities. Mesodiencephalic dopaminergic neurons in the ventral tegmental area (VTA) regulate motivation and reward, whereas those in the substantia nigra (SN) are essential for motor control. Defective VTA dopaminergic transmission has been implicated in schizophrenia, drug addiction and depression whereas dopaminergic neurons in the SN are lost in Parkinson's disease. Maternal immune activation (MIA) leading to in utero inflammation has been proposed to be a risk factor for these disorders, yet it is unclear how this stimulus can lead to the diverse disturbances in dopaminergic-driven behaviors that emerge at different stages of life in affected offspring. Here we report that gestational age is a critical determinant of the subsequent alterations in dopaminergic-driven behavior in rat offspring exposed to lipopolysaccharide (LPS)-induced MIA. Behavioral analysis revealed that MIA on gestational day 16 but not gestational day 12 resulted in biphasic impairments in motor behavior. Specifically, motor impairments were evident in early life, which were resolved by adolescence, but subsequently re-emerged in adulthood. In contrast, reward seeking behaviors were altered in offspring exposed MIA on gestational day 12. These changes were not due to a loss of dopaminergic neurons per se in the postnatal period, suggesting that they reflect functional changes in dopaminergic systems. This highlights that gestational age may be a key determinant of how MIA leads to distinct alterations in dopaminergic-driven behavior across the lifespan of affected offspring.

An Attitudinal Survey of Undergraduate Neuroscience Students Regarding Their Views on the Relevance of Lectures to their Education.

Advances in technology have seen a significant growth in the integration of e-learning into university education. Coupled with this trend are the learning approaches used by "Generation Connected" or GenC students, whose prolific use of digital technology is a defining characteristic. This has resulted in questions being asked as to whether in-class university lecture time is still relevant to university education. Here we conducted a case study with a group of undergraduate neuroscience students to assess their views on the relevance of attending lectures, why they attend or the reasons for non-attendance, and on what makes a good lecture. This is with a view to informing the design of new teaching approaches that may be more beneficial in maximising student engagement, and facilitating learning. The survey instrument was a ten-item questionnaire that collected both qualitative and quantitative data. Over 90% of students were of the view that lectures were beneficial to their learning, while only 4% thought they were an outdated mode of education. Three main themes emerged when students were asked what makes a good lecture: 1. Engagement, 2. Time, and 3. Varied format. We discuss the implications of these findings and suggest how these student views could be woven into the design of teaching approaches to increase the relevance of in-class lecture time in undergraduate neuroscience education.

Viral vector delivery of neurotrophic factors for Parkinson's disease therapy.

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the progressive loss of midbrain dopaminergic neurons, which causes motor impairments. Current treatments involve dopamine replacement to address the disease symptoms rather than its cause. Factors that promote the survival of dopaminergic neurons have been proposed as novel therapies for PD. Several dopaminergic neurotrophic factors (NTFs) have been examined for their ability to protect and/or restore degenerating dopaminergic neurons, both in animal models and in clinical trials. These include glial cell line-derived neurotrophic factor, neurturin, cerebral dopamine neurotrophic factor and growth/differentiation factor 5. Delivery of these NTFs via injection or infusion to the brain raises several practical problems. A new delivery approach for NTFs involves the use of recombinant viral vectors to enable long-term expression of these factors in brain cells. Vectors used include those based on adenoviruses, adeno-associated viruses and lentiviruses. Here we review progress to date on the potential of each of these four NTFs as novel therapeutic strategies for PD, as well as the challenges that have arisen, from pre-clinical analysis to clinical trials. We conclude by discussing recently-developed approaches to optimise the delivery of NTF-carrying viral vectors to the brain.

Knockdown of interleukin-1 receptor 1 is not neuroprotective in the 6-hydroxydopamine striatal lesion rat model of Parkinson's disease.

It is well established that neuroinflammation is associated with the progression of many neurodegenerative diseases, including Parkinson's disease (PD). Activated microglia and elevated levels of pro-inflammatory cytokines such as interleukin-1ß (IL-1ß) have been found in the brain and cerebrospinal fluid of PD patients, suggesting that IL-1ß may be involved in the pathogenesis of this disease. This study aimed to knock down the expression of the interleukin-1 type 1 receptor (IL-1R1) to evaluate any potential therapeutic effect of limiting the action of IL-1ß in the substantia nigra following a unilateral intrastriatal 6-hydroxydopamine (6-OHDA) lesion in rats. Adult Sprague-Dawley rats received intranigral injections of shRNA specific for IL-1R1, followed 2 weeks later by intrastriatal 6-OHDA. Injection of IL-1R1 shRNA did not prevent 6-OHDA-induced loss of motor function or loss of nigral dopamine neurons. IL-1R1 expression was increased in the midbrain following 6-OHDA injection; this effect was attenuated in 6-OHDA-treated animals that had received IL-1R1 shRNA. These data suggest that while IL-1R1 was increased in 6-OHDA-treated animals and reduced following shRNA injection, the neurodegeneration induced by 6-OHDA was not mediated through IL-1R1.

Midbrain dopaminergic neurons: a review of the molecular circuitry that regulates their development.

Dopaminergic (DA) neurons of the ventral midbrain (VM) play vital roles in the regulation of voluntary movement, emotion and reward. They are divided into the A8, A9 and A10 subgroups. The development of the A9 group of DA neurons is an area of intense investigation to aid the generation of these neurons from stem cell sources for cell transplantation approaches to Parkinson's disease (PD). This review discusses the molecular processes that are involved in the identity, specification, maturation, target innervation and survival of VM DA neurons during development. The complex molecular interactions of a number of genetic pathways are outlined, as well as recent advances in the mechanisms that regulate subset identity within the VM DA neuronal pool. A thorough understanding of the cellular and molecular mechanisms involved in the development of VM DA neurons will greatly facilitate the use of cell replacement therapy for the treatment of PD.

BMP2 and GDF5 induce neuronal differentiation through a Smad dependant pathway in a model of human midbrain dopaminergic neurons.

Parkinson's disease is the second most common neurodegenerative disease, and is characterised by the progressive degeneration of the nigrostriatal dopaminergic (DA) system. Current treatments are symptomatic, and do not protect against the DA neuronal loss. One of the most promising treatment approaches is the application of neurotrophic factors to rescue the remaining population of nigrostriatal DA neurons. Therefore, the identification of new neurotrophic factors for midbrain DA neurons, and the subsequent elucidation of the molecular bases of their effects, are important. Two related members of the bone morphogenetic protein (BMP) family, BMP2 and growth differentiation factor 5 (GDF5), have been shown to have neurotrophic effects on midbrain DA neurons both in vitro and in vivo. However, the molecular (signalling pathway(s)) and cellular (direct neuronal or indirect via glial cells) mechanisms of their effects remain to be elucidated. Using the SH-SH5Y human neuronal cell line, as a model of human midbrain DA neurons, we have shown that GDF5 and BMP2 induce neurite outgrowth via a direct mechanism. Furthermore, we demonstrate that these effects are dependent on BMP type I receptor activation of canonical Smad 1/5/8 signalling.

Impacts of gait freeze on quality of life in Parkinson's disease, from the perspectives of patients and their carers.

BACKGROUND: The World Health Organisation (WHO) reports that morbidity and mortality due to Parkinson's disease (PD) are increasing faster than for other neurodegenerative conditions. People with Parkinson's (PwP) present with a variety of motor symptoms, such as tremor, bradykinesia, and rigidity. Freezing of gait (FoG) is a significant motor symptom that manifests as temporary episodes of inability to move one's feet, despite the intention to walk. AIMS: This study examined the impact of FoG on quality of life (QoL) within an Irish cohort of PwP, from the perspectives of both PwP and their carers, using validated questionnaires that had been adapted for online use. METHODS: PwP and their carers were recruited by outreach to the Irish Parkinson's Community. Anonymous online questionnaires were distributed, which combined a demographic survey with several clinically validated surveys, including Freezing of Gait Questionnaire (FoG-Q), Parkinson's Disease Questionnaire 8 (PDQ-8), and Parkinson's Disease Carer Questionnaire (PDQ-C). RESULTS: There was a strong correlation (p < 0.001) between severity of FoG and lower QoL among PwP. Significant correlation was also found between FoG severity and several motor symptoms, such as postural instability and difficulty with balance, and non-motor symptoms, such as cognitive changes and pain/discomfort. FoG severity correlated with disease progression. Significant correlation was also found between FoG and symptoms, as assessed from the perspective of the patients' carers. CONCLUSIONS: This study shows that FoG is a significant detriment to the QoL of PwP, from the perspectives of patients and carers. This method of assessing FoG and QoL using online questionnaires has potential to enhance the reach and flexibility of this type of research. These findings will inform future studies on larger cohorts and highlight unmet clinical needs in PwP.

Intensive training programme improves handwriting in a community cohort of people with Parkinson's disease.

BACKGROUND: People with Parkinson's disease (PwP) often report problems with their handwriting before they receive a formal diagnosis. Many PwP suffer from deteriorating handwriting throughout their illness, which has detrimental effects on many aspects of their quality of life. AIMS: To assess a 6-week online training programme aimed at improving handwriting of PwP. METHODS: Handwriting samples from a community-based cohort of PwP (n = 48) were analysed using systematic detection of writing problems (SOS-PD) by two independent raters, before and after a 6-week remotely monitored physiotherapy-led training programme. Inter-rater variability on multiple measures of handwriting quality was analysed. The handwriting data was analysed using pre-/post-design in the same individuals. Multiple aspects of the handwriting samples were assessed, including writing fluency, transitions between letters, regularity in letter size, word spacing, and straightness of lines. RESULTS: Analysis of inter-rater reliability showed high agreement for total handwriting scores and letter size, as well as speed and legibility scores, whereas there were mixed levels of inter-rater reliability for other handwriting measures. Overall handwriting quality (p = 0.001) and legibility (p = 0.009) significantly improved, while letter size (p = 0.012), fluency (p = 0.001), regularity of letter size (p = 0.009), and straightness of lines (p = 0.036) were also enhanced. CONCLUSIONS: The results of this study show that this 6-week intensive remotely-monitored physiotherapy-led handwriting programme improved handwriting in PwP. This is the first study of its kind to use this tool remotely, and it demonstrated that the SOS-PD is reliable for measuring handwriting in PwP.

Human α-synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageing.

Parkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α-synuclein (αSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that ageing increases αSyn expression in DA neurons and that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To model this, adult female Sprague-Dawley rats received a unilateral intranigral injection of adeno-associated viral (AAV) vector carrying wild-type human αSyn (AAV-αSyn) or control vector (AAV-Null). AAV-αSyn induced no detrimental effects on motor behaviour, but there was expression of human wild-type αSyn throughout the midbrain and ipsilateral striatum at 20 weeks post-surgery. Microarray analysis revealed that the gene most-upregulated in the ipsilateral SN of the AAV-αSyn group was the SKI Family Transcriptional Corepressor 1 (SKOR1). Bioenergetic state analysis of mitochondrial function found that SKOR1 overexpression reduced the maximum rate of cellular respiration in SH-SY5Y cells. Furthermore, experiments in SH-SY5Y cells revealed that SKOR1 overexpression impaired neurite growth to the same extent as αSyn, and inhibited BMP-SMAD-dependent transcription, a pathway that promotes DA neuronal survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent of αSyn-induced SKOR1 expression may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which ageing-related increases in αSyn may influence molecular mechanisms important for the maintenance of neuronal integrity.

A role for interleukin-1ß in determining the lineage fate of embryonic rat hippocampal neural precursor cells.

Neurogenesis occurs in the hippocampus of the developing and adult brain due to the presence of multipotent stem cells and restricted precursor cells at different stages of differentiation. It has been proposed that they may be of potential benefit for use in cell transplantation approaches for neurodegenerative disorders and trauma. Prolonged release of interleukin-1ß (IL-1ß) from activated microglia has a deleterious effect on hippocampal neurons and is implicated in the impaired neurogenesis and cognitive dysfunction associated with aging, Alzheimer's disease and depression. This study assessed the effect of IL-1ß on the proliferation and differentiation of embryonic rat hippocampal NPCs in vitro. We show that IL-1R1 is expressed on proliferating NPCs and that IL-1ß treatment decreases cell proliferation and neurosphere growth. When NPCs were differentiated in the presence of IL-1ß, a significant reduction in the percentages of newly-born neurons and post-mitotic neurons and a significant increase in the percentage of astrocytes was observed in these cultures. These effects were attenuated by IL-1 receptor antagonist. These data reveal that IL-1ß exerts an anti-proliferative, anti-neurogenic and pro-gliogenic effect on embryonic hippocampal NPCs, which is mediated by IL-1R1. The present results emphasise the consequences of an inflammatory environment during NPC development, and indicate that strategies to inhibit IL-1ß signalling may be necessary to facilitate effective cell transplantation approaches or in conditions where endogenous hippocampal neurogenesis is impaired.

Diet quality, sleep and quality of life in Parkinson's disease: a cross-sectional study.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterised by motor and non-motor symptoms that impact quality of daily life, including diet and sleep. However, relatively little is known about dietary intake and quality in people with PD (PwP). Lifestyle factors, and how they relate to diet, are also insufficiently understood. The aims of this study were to investigate dietary intake and quality, sleep and quality of life in PwP, and to explore the relationships between these factors. METHODS: Forty-five community-dwelling participants with PD (n = 45) were recruited to this cross-sectional study through the Cork Parkinson's Association, Ireland. Dietary intake was assessed using the EPIC food frequency questionnaire, and diet quality was assessed using the Healthy Diet Indicator. Dietary intakes were compared to Irish RDAs for adults > 65 years. Sleep duration and quality were subjectively measured using the PD Sleep Scale and Pittsburgh sleep quality index and objectively measured by actigraphy in a subset of participants (n = 27). QOL was measured using the validated PDQ-39 questionnaire. RESULTS: Energy intake in PwP was significantly higher than that of the general population (2013 vs 1755 kcal/d, p = 0.01), despite their lower mean BMI (25.9 vs 27.7 kg/m2, p = 0.02). Intakes of carbohydrate, protein and fruits and vegetables were significantly higher in PwP compared to recommended and population intakes (all p < 0.01), but fibre intake was significantly lower than recommended (17.3 vs 25 g/d, p [Formula: see text] 0.05). Seventy-eight percent of participants had poor dietary quality, and poor sleep quality was associated with poor QOL. CONCLUSIONS: Carbohydrates, protein, fruit and vegetable intakes were greater in PwP than population norms, but overall diet quality was low. Interventions to improve dietary and lifestyle factors may improve health and QOL in PwP.

A combined proteomics and bioinformatics analysis of ZNHIT1-interacting proteins reveals a significant enrichment in proteins associated with mitochondrial function.

Adenosine 5'-triphosphate (ATP) is the principal source of cellular energy, which is essential for neuronal health and maintenance. Parkinson's disease (PD) and other neurodegenerative disorders are characterised by impairments in mitochondrial function and reductions in cellular ATP levels. Thus there is a need to better understand the biology of intracellular regulators of ATP production, in order to inform the development of new neuroprotective therapies for diseases such as PD. One such regulator is Zinc finger HIT-domain containing protein 1 (ZNHIT1). ZNHIT1 is an evolutionarily-conserved component of a chromatin-remodelling complex, which has been recently shown to increase cellular ATP production in SH-SY5Y cells and to protect against impairments in mitochondrial function caused by alpha-synuclein, a protein which is integral to PD pathophysiology. This effect of ZNHIT1 on cellular ATP production is thought to be due to increased expression of genes associated with mitochondrial function, but it is also possible that ZNHIT1 regulates mitochondrial function by binding to mitochondrial proteins. To examine this question, we performed a combined proteomics and bioinformatics analysis to identify ZNHIT1-interacting proteins in SH-SY5Y cells. We report that ZNHIT1-interacting proteins are significantly enriched in multiple functional categories, including mitochondrial transport, ATP synthesis and ATP-dependent activity. Furthermore we also report that the correlation between ZNHIT1 and dopaminergic markers is reduced in the PD brain. These data suggest that the reported beneficial effects of ZNHIT1 on ATP production may be mediated, at least in part, by its direct interaction with mitochondrial proteins and suggest that potential alterations in ZNHIT1 in PD may contribute to the known impairments in ATP generation in midbrain dopaminergic neurons in PD.

Transplantation of novel human GDF5-expressing CHO cells is neuroprotective in models of Parkinson's disease.

Growth/differentiation factor 5 (GDF5) is a neurotrophic factor that promotes the survival of midbrain dopaminergic neurons in vitro and in vivo and as such is potentially useful in the treatment of Parkinson's disease (PD). This study shows that a continuous supply of GDF5, produced by transplanted GDF5-overexpressing CHO cells in vivo, has neuroprotective and neurorestorative effects on midbrain dopaminergic neurons following 6-hydroxydopamine (6-OHDA)-induced lesions of the adult rat nigrostriatal pathway. It also increases the survival and improves the function of transplanted embryonic dopaminergic neurons in the 6-OHDA-lesioned rat model of PD. This study provides the first proof-of-principle that sustained delivery of GDF5 in vivo may be useful in the treatment of PD.

Growth differentiation factor 5: a neurotrophic factor with neuroprotective potential in Parkinson's disease.

Parkinson's disease is the most common movement disorder worldwide, affecting over 6 million people. It is an age-related disease, occurring in 1% of people over the age of 60, and 3% of the population over 80 years. The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra, and their axons, which innervate the striatum, resulting in the characteristic motor and non-motor symptoms of Parkinson's disease. This is paralleled by the intracellular accumulation of α-synuclein in several regions of the nervous system. Current therapies are solely symptomatic and do not stop or slow disease progression. One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum, to protect the remaining dopaminergic neurons of the nigrostriatal pathway. However, clinical trials of two well-established neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have failed to meet their primary end-points. This failure is thought to be at least partly due to the downregulation by α-synuclein of Ret, the common co-receptor of glial cell line-derived neurorophic factor and neurturin. Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors, that signals through the Ret-independent canonical Smad signaling pathway. Here, we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson's disease. We discuss new work on growth/differentiation factor 5's mechanisms of action, as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in the α-synuclein rat model of Parkinson's disease. These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson's disease.