Role of brain-derived neurotrophic factor in Huntington's disease
Introduction
Huntington's disease (HD) is a fatal, dominantly inherited, neurodegenerative disorder that usually onsets in midlife, and is characterised by psychiatric, cognitive and motor dysfunctions. It is due to an excessive repetition of the CAG trinucleotide in exon 1 of the huntingtin gene (Huntington's Disease Collaborative Research Group, 1993) which causes the production of a protein bearing a polyglutamine expanded tract in its N-terminus. The huntingtin mutation leads to widespread brain neurodegeneration, with cell loss mainly in the striatum and cerebral cortex (Reiner et al., 1988), although neuronal abnormalities are also found in many other brain regions (Rosas et al., 2003).
Results from various laboratories suggest that brain-derived neurotrophic factor (BDNF) is involved in the development of the human disease. BDNF was discovered in 1982 (Barde et al., 1982), as the second in a family of molecules with neurotrophic activities whose first identified member was nerve growth factor (NGF) (Levi-Montalcini and Hamburger, 1951). Although widely expressed in the adult mammalian central nervous system (CNS), BDNF is particularly abundant in the hippocampus and cerebral cortex where it is anterogradely transported to its striatal targets via the corticostriatal afferents (Hofer et al., 1990, Altar et al., 1997, Baquet et al., 2004).
Striatal neurons in the brain require BDNF for their activity and survival. Approximately 95% of striatal BDNF is actually of cortical origin, with the rest being produced in the substantia nigra and delivered to the striatum (Altar et al., 1997, Baquet et al., 2004). BDNF expression increases during brain development, peaks after birth (Maisonpierre et al., 1990, Friedman et al., 1991, Huntley et al., 1992 Friedman et al., 1998; Schecterson and Bothwell, 1992; Kolbeck et al., 1999, Baquet et al., 2004), and does not seem to decline with age, thus suggesting that it plays an essential role in the adult CNS (Lapchak et al., 1993; Narisawa-Saito and Nawa, 1996; Katoh-Semba et al., 1997, Katoh-Semba et al., 1998).
BDNF protein is transduced from a single, highly complex gene that carries a number of alternatively used promoters to generate a developmental, tissue-specific and stimulus-induced pattern of BDNF expression (Timmusk et al., 1993, Timmusk et al., 1994, Timmusk et al., 1995, Aid et al., 2007, Liu et al., 2006). The activity of this large regulatory region becomes progressively more complex and presumably more specialised in humans (Liu et al., 2005).
The fact that BDNF has survival promoting activity on the striatal neurons that die in HD has led to the idea that reduced endogenous trophic support may contribute to disease onset and/or progression. This hypothesis has aroused interest in BDNF and/or BDNF mimetics as potential therapeutic agents, and this has been intensified by reports of reduced BDNF levels in the cerebral cortex and striatum of people with HD (Zuccato et al., 2001), as well as in many mouse and cell models of the disease (see Cattaneo et al., 2005 for a review). Furthermore, although no underlying molecular mechanism has been proposed to explain reduced neurotrophic support in other neurological diseases such a Parkinson's disease (PD) or Alzheimer's disease (AD), it is known that the huntingtin mutation in HD reduces the transcriptional activity of the BDNF promoters, thus reducing the transcription of the BDNF gene and decreasing protein production in the cerebral cortex (Zuccato et al., 2001, Zuccato et al., 2003, Zuccato et al., 2005a). Finally, a selective defect in the transport of BDNF protein from cortex to striatum has also been proposed (Gauthier et al., 2004).
The impact of BDNF depletion in HD mice has been tested in experiments in which the levels of endogenous BDNF have been further reduced experimentally, with the consequence of lowering the age of onset and exacerbating the motor dysfunction. The observed neuropathology correlates with morphological alterations in the brain, a finding that confirms the pivotal role of BDNF in the specific degeneration of striatal neurons (Canals et al., 2004). Early experiments in which BDNF was administered in mouse models of HD indicate that BDNF may be beneficial to striatal neurons, although delivery strategies and BDNF bioavailability need to be further improved. More recently, it has been found that administering BDNF to HD mice by means of an osmotic minipump increases the number of striatal enkephalinergic neurons, the most affected population in HD (Canals et al., 2004), thus confirming the possibility that delivering BDNF or increasing endogenous BDNF production may stop or delay the progression of the human disease.
This review discusses the evidence indicating that cortical BDNF is a critical survival factor for the striatal neurons that die in HD. It describes the available data showing the negative influence of BDNF gene inactivation on the performance of striatal neurons in control mice, considers the molecular relationship between huntingtin and BDNF, describes the mechanism by which normal but not mutant huntingtin promotes BDNF production and axonal transport, and discusses the evidence indicating a worse HD phenotype in animal models lacking one BDNF allele. We present the case that the discovery of the mechanisms by which wild-type huntingtin controls the transcription of the BDNF and other neuronal genes may be exploited in drug-screening strategies aimed at identifying compounds capable of acting as huntingtin mimetics. Finally, we summarise attempts to deliver BDNF in HD animal models and the strategies available for increasing its level in human HD.
Section snippets
BDNF, a member of the neurotrophin family
BDNF is an abundant member of the NGF family in mammalian brain. By binding specific receptors such as tyrosine receptor kinase B (TrkB) and p75 neurotrophin receptor (p75NTR), BNDF acts in a paracrine and autocrine manner to control a variety of brain processes, including the growth, development, differentiation and maintenance of neuronal systems, neuronal plasticity, synaptic activity and neurotransmitter-mediated activities (see Chao, 2003, and Binder and Scharfman, 2004, for reviews).
Like
Production of BDNF is stimulated by wild-type huntingtin: physiology and mechanism
We will here review the evidence linking BDNF gene transcription to wild-type huntingtin, the protein whose mutation causes HD, as well as the data demonstrating that a well-known DNA regulatory sequence located within the BDNF promoter represents the first identified downstream molecular target of wild-type huntingtin activity. We will also review the mechanism by which wild-type huntingtin facilitates BDNF gene transcription and summarise the evidence showing that the same mechanism underlies
BDNF is reduced in HD models
A large number of studies have found reduced BDNF levels in HD, which implies that this may put the target striatal neurons and possibly the corticostriatal circuitry at risk (Table 1). This hypothesis is supported by the fact that the neuronal degeneration in human HD mainly affects the striatum and cerebral cortex (Reiner et al., 1988, Rosas et al., 2003), and cortical atrophy may be present even before the onset of symptoms (Rosas et al., 2005). Reduced BDNF levels have also been observed in
BDNF vesicle transport is enhanced by wild-type huntingtin
Huntingtin is predominantly found in the cytoplasm of neurons and is enriched in compartments containing vesicle-associated proteins (DiFiglia et al., 1995). Moreover, wild-type huntingtin is antero- and retrogradely transported in rat sciatic nerve axons, which is consistent with a vesicle association (Block-Galarza et al., 1997). Importantly, huntingtin interacts with the scaffolding proteins involved in axonal transport, such as huntingtin-associated protein 1 (HAP1), and with the dynactin
Evidence of reduced BDNF transport in HD
To establish whether the presence of a polyglutamine expansion in huntingtin affects BDNF transport in HD, BDNF vesicle velocity was measured in heterozygous and homozygous mutant huntingtin knock-in cells in which 109 CAG repeats are inserted in the endogenous huntingtin locus, thus creating a situation similar to that found in HD patients. Further biochemical studies of mutant huntingtin knock-in cells, mice and HD postmortem tissues indicated that the complex driving BDNF vesicles is altered
BDNF levels in HD patients
As described above, analyses of BDNF levels in the striatum of HD mice have generated two different nonmutually exclusive data sets, indicating the possibility that reduced BDNF in striatum is the result of decreased BDNF production in the cortex and decreased transport of this neurotrophin from the cortex to striatum. The first envisions wild-type huntingtin participating in controlling the transcription of the BDNF gene in cerebral cortex by acting at the level of promoter II, thus allowing
BDNF depletion enhances neuropathology and disease onset in HD mice
Previous data indicate that the deficit in striatal BDNF in HD may be due to reduced BDNF gene transcription in the cerebral cortex or reduced BDNF vesicle transport (or both). As described in Section 2.3, the downregulation of endogenous cortical BDNF highlights a link between cortical BDNF levels and specific aspects of HD attributable to decreased BDNF levels (Baquet et al., 2004). To investigate whether the downregulation of endogenous BDNF can influence disease onset and/or progression,
TrkB levels in HD
In order to exert its biological activity, BDNF binds to TrkB receptors, and a number of studies have indicated that TrkB is modulated after neuronal damage: for example, TrkB mRNA is increased in cortical and striatal neurons after excitotoxic lesions (Canals et al., 1999, Checa et al., 2001), and reduced TrkB levels have been associated with neurodegeneration in AD (Connor et al., 1996, Connor et al., 1997, Allen et al., 1999, Ferrer et al., 1999, Soontornniyomkij et al., 1999, Savaskan et
A role for BDNF polymorphisms?
As stated in Section 5.1, a valine-to-methionine substitution at position 66 (Val66Met BDNF) is a known polymorphism of the human BDNF gene that is located in the 5′ pro-BDNF sequence encoding the precursor peptide (pro-BDNF), which is proteolytically cleaved to form the mature protein. This BDNF polymorphism does not affect mature BDNF protein function, but it has recently been shown that it dramatically alters the intracellular trafficking and packaging of pro-BDNF, and consequently the
BDNF: a therapeutic path for Huntington's disease?
A number of studies have shown that BDNF is a potent neurotrophic factor for GABA-ergic striatal neurons. When administered to cultured striatal neurons, it increases their cellular GABA content, the frequency of parvalbumin and calbindin neurons, and the levels of neuropeptide Y and somatostatin (Mizuno et al., 1994; Ventimiglia et al., 1995). In addition, a study by Nakao et al. (1995) showed that BDNF promoted the survival of DARPP-32 positive neurons and, as DARPP-32 is a specific marker of
Conclusion
The findings described in this paper indicate that BDNF is essential for maintaining the corticostriatal pathway, and the cortical BDNF is required for the survival and differentiation of striatal neurons under both physiological and pathological conditions. More importantly, they show that the normal huntingtin protein, whose mutation causes HD, is involved in the physiological control of BDNF synthesis and transport in the brain: it sustains cortical BDNF gene transcription and drives BDNF
Acknowledgements
The authors thanks Drs. Paola Conforti, Manuela Marullo and Dorotea Rigamonti for their comments during the preparation of the manuscript. The work of the authors described in this review is supported by the Huntington's Disease Society of America (USA), Telethon (Italy), The Hereditary Disease Foundation (USA), The HighQ Foundation (USA), Fondazione Cariplo (Italy), Ministero dell’Istruzione dell’Università e della Ricerca (Italy) and NeuroNE (Network of Excellence on Neurodegenerative
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